Phosphonate compounds having immuno-modulatory activity

ABSTRACT

The invention is related to phosphonate substituted compounds having immuno-modulatory activity, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

This non-provisional application claims the benefit of priority under 35U.S.C. § 119(e) from U.S. Provisional Patent Application Ser. Nos.60/465,424, 60/465,373, 60/465,420, 60/465,380, 60/465,433, 60/465,481,60/465,377, 60/465,581, 60/465,532, 60/465,844, 60/465,531, and60/465,574, all filed Apr. 25, 2003; and to U.S. Provisional PatentApplication Ser. Nos. 60/493,303, 60/493,310, 60/493,309, and60/493,302, all filed Aug. 7, 2003; and to U.S. Provisional PatentApplication Ser. Nos. 60/495,533, 60/495,529, 60/495,455, 60/495,537,60/495,456, 60/495,398, 60/495,425, 60/495,427, 60/495,661, 60/495,393,60/495,416, 60/495,614, and 60/495,417, all filed Aug. 15, 2003; and toU.S. Provisional Patent Application Ser. Nos. 60/514,054, 60/513,971,60/514,394, 60/513,975, 60/514,453, 60/514,202, 60/513,948, 60/514,424,60/514,280, 60/514,144, 60/513,979, 60/514,075, 60/513,946, 60/514,051,60/514,161, 60/514,325, 60/514,044, 60/514,201, 60/514,522, 60/514,140,60/514,175, 60/514,113, 60/513,562, 60/513,592, 60/513,563, 60/513,579,60/513,561, 60/513,589, 60/513,593, 60/513,588, 60/514,258, 60/514,021,and 60/514,298, all filed Oct. 24, 2003; and to U.S. Provisional PatentApplication Ser. Nos. 60/532,230, 60/531,960, 60/532,160, 60/531,940,and 60/531,932, all filed Dec. 1, 2003; and to U.S. Provisional PatentApplication Ser. No. 60/532,591, filed Dec. 23, 2003; and to U.S.Provisional Patent Application Ser. No. 60/536,005, filed Jan. 12, 2004.The entirety of all Provisional Applications listed above areincorporated herein by reference.

FIELD OF THE INVENTION

The invention relates generally to compounds with immuno-modulatory(e.g., immunosuppressant) activity.

BACKGROUND OF THE INVENTION

Improving the delivery of drugs and other agents to target cells andtissues has been the focus of considerable research for many years.Though many attempts have been made to develop effective methods forimporting biologically active molecules into cells, both in vivo and invitro, none has proved to be entirely satisfactory. Optimizing theassociation of the inhibitory drug with its intracellular target, whileminimizing intercellular redistribution of the drug, e.g., toneighboring cells, is often difficult or inefficient.

Most agents currently administered to a patient parenterally are nottargeted, resulting in systemic delivery of the agent to cells andtissues of the body where it is unnecessary, and often undesirable. Thismay result in adverse drug side effects, and often limits the dose of adrug (e.g., glucocorticoids and other anti-inflammatory drugs) that canbe administered. By comparison, although oral administration of drugs isgenerally recognized as a convenient and economical method ofadministration, oral administration can result in either (a) uptake ofthe drug through the cellular and tissue barriers, e.g., blood/brain,epithelial, cell membrane, resulting in undesirable systemicdistribution, or (b) temporary residence of the drug within thegastrointestinal tract. Accordingly, a major goal has been to developmethods for specifically targeting agents to cells and tissues. Benefitsof such treatment includes avoiding the general physiological effects ofinappropriate delivery of such agents to other cells and tissues, suchas uninfected cells.

Autoimmune diseases and transplantation rejection remain major publichealth problems worldwide. Although drugs with immunosuppressiveactivity are in wide use and have shown effectiveness, there clinicalusefulness has been limited due to their toxicity and other sideeffects. Currently there is a need for new immunosuppressant agents,i.e. drugs, having improved immunosuppressant activity andpharmacokinetic properties, improved oral bioavailability, greaterpotency, and extended effective half-life in vivo. New immunosuppressantagents should have fewer side effects, less complicated dosingschedules, and/or be orally active.

SUMMARY OF THE INVENTION

Intracellular targeting may be achieved by methods and compositions thatallow accumulation or retention of biologically active agents insidecells. The present invention provides novel phosphonate containinganalogs of immuno-modulatory (e.g., immunosuppressant) compounds. Thesecompounds possess the utilities of the related immuno-modulatorycompounds, but due to the presence of the phosphonate group(s) theytypically provide cellular accumulation of the phosphonate compound.Thus, compounds of the invention may demonstrate improvedimmuno-modulatory properties, pharmacokinetic properties, oralbioavailability, potency, or extended effective half-life in vivo, or acombination thereof. The compounds of the invention may also havedistinct resistance profiles, fewer side effects, less complicateddosing schedules, or have increased oral activity.

The present invention relates generally to the accumulation or retentionof therapeutic compounds inside cells. The invention is moreparticularly related to attaining high concentrations ofphosphonate-containing molecules in target cells. Such effectivetargeting may be applicable to a variety of therapeutic formulations andprocedures.

Accordingly, in one embodiment the invention provides a compound of theinvention which is a conjugate comprising an immuno-modulatory compound(e.g., an immunosuppressant compound) linked to one or more phosphonategroups.

Compositions of the invention include immuno-modulatory compounds havingat least one phosphonate group. Accordingly, in one embodiment theinvention provides a conjugate comprising an immuno-modulatory compound(e.g., an immunosuppressant compound) linked to one or more phosphonategroups or a pharmaceutically acceptable salt thereof.

In another embodiment the invention provides a compound of any one offormulae 500-547:

that is substituted with one or more phosphonate groups either directlyor indirectly through a linker; and that is optionally substituted withone or more groups A⁰; or a pharmaceutically acceptable salt thereof,wherein:

A⁰ is A¹, A² or W³ with the proviso that the conjugate includes at leastone A¹;

A¹ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;and when Y² joins two phosphorous atoms Y² can also be C(R²)(R²);

R^(x) is independently H, R¹, R², W³, a protecting group, or theformula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y^(x))(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x),or —N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO_(M2)R⁵, or —SO_(M2)W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another embodiment the invention provides a compound of the formula:

[DRUG]-(A⁰)_(nn)

or a pharmaceutically acceptable salt thereof wherein;

DRUG is a compound of any one of formulae 500-547;

nn is 1, 2, or 3;

wherein:

A⁰ is A¹, A² or W³ with the proviso that the conjugate includes at leastone A¹;

A¹ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;and when Y² joins two phosphorous atoms Y² can also be C(R²)(R²);

R^(x) is independently H, R¹, R², W³, a protecting group, or theformula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y;

R^(3c) is R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO_(M2)R⁵, or —SO_(M2)W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another embodiment the invention provides a compound of any one offormulae 1-151:

wherein:

A⁰ is A¹;

A¹ is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;and when Y² joins two phosphorous atoms Y² can also be C(R²)(R²);

R^(x) is independently H, R², W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

each X⁵⁰ is independently hydrogen, F, Cl, CF₃, CN, methyl, ortert-butyl;

X⁵¹ is hydrogen, halo, trifluoromethyl, (C1-C3)alkyl, cyano, or(C1-C3)alkoxy;

X⁵² is hydrogen, fluoro, chloro, bromo, methyl, or trifluoromethyl;

X⁵³ is —O—, or —S—;

X⁵⁴ and X⁵⁵ are independently selected from hydrogen or a C₁-C₁₈ acyl;

X⁵⁶ is hydrogen, a C₁-C₁₈ acyl, or

or X⁵⁴ is hydrogen and together X⁵⁵ and X⁵⁶ are

X⁵⁷ is H, amino, hydroxy, or a halogen selected from Cl and Br;

X⁵⁸ is hydrogen, F, Cl, CF3, cyano, methyl, or t-butyl;

X⁵⁹ is hydrogen, CH₂OH;

X⁶⁰ is CO(CH₂)₆CONMe(CH₂)2_(s)O₃H;

X⁶² is methyl, chloro, or trifluoromethyl;

X⁶³ is H, methyl, ethyl, cyclopropyl, vinyl, or trifluoromethyl;

X⁶⁴ is H, methyl, ethyl, cyclopropyl, chloro, vinyl, allyl,3-methyl-1-buten-1-yl;

X⁶⁵ is hydrogen or F; and

Ar is aryl or heteroaryl.

The invention provides a pharmaceutical composition comprising aneffective amount of a compound of the invention, or a pharmaceuticallyacceptable salt thereof, in combination with a pharmaceuticallyacceptable diluent or carrier.

This invention pertains to a method of increasing cellular accumulationand retention of drug compounds, thus improving their therapeutic anddiagnostic value, comprising linking the compound to one or morephosphonate groups.

The invention also provides a method for the maintenance ofimmunosuppression, for example, following transplant surgery, comprisingadministering to an animal (e.g. a mammal) an effective amount of acompound of the invention.

The invention also provides a method for modulating an immune responsein vitro or in vivo comprising contacting a sample in need of suchtreatment with a compound of the invention.

The invention also provides a method of inhibiting an immune response inan animal (e.g. a mammal), comprising administering an effective amountof a compound of the invention to the animal.

The invention also provides a method of treating the symptoms or effectsof an autoimmune disease (e.g. psoriasis, rheumatoid arthritis, lupuserythematosus, multiple sclerosis, diabetes, Chron's disease, etc.) inan animal (e.g. a mammal), comprising administering an effective amountof a compound of the invention to the animal.

The invention also provides a method of treating the symptoms or effectsof transplant rejection in an animal (e.g. a mammal), comprisingadministering an effective amount of a compound of the invention to theanimal.

The invention also provides a method for inhibiting the proliferation ofhuman T cells and/or downregulating the production of Th1 or Th2 typecytokines in an animal (e.g. a mammal) comprising administering acompound of the invention to the animal.

The invention also provides a method for treating atopic dermatitis inan animal (e.g. a mammal), comprising administering an effective amountof a compound of the invention to the animal.

The invention also provides a method for inhibiting one or moreT-lymphocyte functions in an animal (e.g. a mammal), comprisingadministering an effective amount of a compound of the invention to theanimal.

The invention also provides a method for inhibiting dihydroorotatedehydrogenase in an animal (e.g. a mammal), comprising administering aneffective amount of a compound of the invention to the animal.

The invention also provides a compound of the invention for use inmedical therapy (preferably for use in the maintenance ofimmunosuppression following transplant surgery, inhibiting an immuneresponse, treating an autoimmune disease, treating atopic dermatitis,inhibiting the proliferation of human T cells, or downregulating theproduction of Th1 or Th2 type cytokines), as well as the use of acompound of the invention for the manufacture of a medicament useful formaintenance of immunosuppression following transplant surgery in ananimal (e.g. a mammal). The invention also provides the use of acompound of the invention for the manufacture of a medicament useful forinhibiting an immune response in an animal (e.g. a mammal). Theinvention also provides the use of a compound of the invention for themanufacture of a medicament useful for treating an autoimmune disease inan animal (e.g. a mammal). The invention also provides the use of acompound of the invention for the manufacture of a medicament useful forinhibiting the proliferation of human T cells or downregulating theproduction of Th1 or Th2 type cytokines in an animal.

The invention also provides a method for the maintenance ofimmunosuppression, for example, following transplant surgery, comprisingadministering to an animal (e.g., a mammal) an effective amount of acompound of the invention.

The invention also provides processes and novel intermediates disclosedherein which are useful for preparing compounds of the invention. Someof the compounds of the invention are useful to prepare other compoundsof the invention.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain claims of the invention,examples of which are illustrated in the accompanying structures andformulas. While the invention will be described in conjunction with theenumerated claims, it will be understood that they are not intended tolimit the invention to those claims. On the contrary, the invention isintended to cover all alternatives, modifications, and equivalents,which may be included within the scope of the present invention asdefined by the claims.

DEFINITIONS

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When tradenames are used herein, applicants intend to independentlyinclude the tradename product and the active pharmaceuticalingredient(s) of the tradename product.

“Bioavailability” is the degree to which the pharmaceutically activeagent becomes available to the target tissue after the agent'sintroduction into the body. Enhancement of the bioavailability of apharmaceutically active agent can provide a more efficient and effectivetreatment for patients because, for a given dose, more of thepharmaceutically active agent will be available at the targeted tissuesites.

The terms “phosphonate” and “phosphonate group” include functionalgroups or moieties within a molecule that comprises a phosphorous thatis 1) single-bonded to a carbon, 2) double-bonded to a heteroatom, 3)single-bonded to a heteroatom, and 4) single-bonded to anotherheteroatom, wherein each heteroatom can be the same or different. Theterms “phosphonate” and “phosphonate group” also include functionalgroups or moieties that comprise a phosphorous in the same oxidationstate as the phosphorous described above, as well as functional groupsor moieties that comprise a prodrug moiety that can separate from acompound so that the compound retains a phosphorous having thecharacteristics described above. For example, the terms “phosphonate”and “phosphonate group” include phosphonic acid, phosphonic monoester,phosphonic diester, phosphonamidate, and phosphonthioate functionalgroups. In one specific embodiment of the invention, the terms“phosphonate” and “phosphonate group” include functional groups ormoieties within a molecule that comprises a phosphorous that is 1)single-bonded to a carbon, 2) double-bonded to an oxygen, 3)single-bonded to an oxygen, and 4) single-bonded to another oxygen, aswell as functional groups or moieties that comprise a prodrug moietythat can separate from a compound so that the compound retains aphosphorous having such characteristics. In another specific embodimentof the invention, the terms “phosphonate” and “phosphonate group”include functional groups or moieties within a molecule that comprises aphosphorous that is 1) single-bonded to a carbon, 2) double-bonded to anoxygen, 3) single-bonded to an oxygen or nitrogen, and 4) single-bondedto another oxygen or nitrogen, as well as functional groups or moietiesthat comprise a prodrug moiety that can separate from a compound so thatthe compound retains a phosphorous having such characteristics.

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system generates the drug substance, i.e.active ingredient, as a result of spontaneous chemical reaction(s),enzyme catalyzed chemical reaction(s), photolysis, and/or metabolicchemical reaction(s). A prodrug is thus a covalently modified analog orlatent form of a therapeutically-active compound.

“Prodrug moiety” refers to a labile functional group which separatesfrom the active inhibitory compound during metabolism, systemically,inside a cell, by hydrolysis, enzymatic cleavage, or by some otherprocess (Bundgaard, Hans, “Design and Application of Prodrugs” in ATextbook of Drug Design and Development (1991), P. Krogsgaard-Larsen andH. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymeswhich are capable of an enzymatic activation mechanism with thephosphonate prodrug compounds of the invention include, but are notlimited to, amidases, esterases, microbial enzymes, phospholipases,cholinesterases, and phosphotases. Prodrug moieties can serve to enhancesolubility, absorption and lipophilicity to optimize drug delivery,bioavailability and efficacy. A prodrug moiety may include an activemetabolite or drug itself.

Exemplary prodrug moieties include the hydrolytically sensitive orlabile acyloxymethyl esters —CH₂C(═O)R⁹ and acyloxymethyl carbonates—CH₂C(═O)OR⁹ where R⁹ is C₁-C₆ alkyl, C₁-C₆ substituted alkyl, C₆-C₂₀aryl or C₆-C₂₀ substituted aryl. The acyloxyalkyl ester was first usedas a prodrug strategy for carboxylic acids and then applied tophosphates and phosphonates by Farquhar et al. (1983) J. Pharm. Sci. 72:324; also U.S. Pat. Nos. 4,816,570, 4,968,788, 5,663,159 and 5,792,756.Subsequently, the acyloxyalkyl ester was used to deliver phosphonicacids across cell membranes and to enhance oral bioavailability. A closevariant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester(carbonate), may also enhance oral bioavailability as a prodrug moietyin the compounds of the combinations of the invention. An exemplaryacyloxymethyl ester is pivaloyloxymethoxy, (POM) —CH₂C(═O)C(CH₃)₃. Anexemplary acyloxymethyl carbonate prodrug moiety ispivaloyloxymethylcarbonate (POC)—CH₂C(═O)OC(CH₃)₃.

The phosphonate group may be a phosphonate prodrug moiety. The prodrugmoiety may be sensitive to hydrolysis, such as, but not limited to apivaloyloxymethyl carbonate (POC) or POM group. Alternatively, theprodrug moiety may be sensitive to enzymatic potentiated cleavage, suchas a lactate ester or a phosphonamidate-ester group.

Aryl esters of phosphorus groups, especially phenyl esters, are reportedto enhance oral bioavailability (De Lombaert et al. (1994) J. Med. Chem.37: 498). Phenyl esters containing a carboxylic ester ortho to thephosphate have also been described (Khamnei and Torrence, (1996) J. Med.Chem. 39:4109-4115). Benzyl esters are reported to generate the parentphosphonic acid. In some cases, substituents at the ortho- orpara-position may accelerate the hydrolysis. Benzyl analogs with anacylated phenol or an alkylated phenol may generate the phenoliccompound through the action of enzymes, e.g., esterases, oxidases, etc.,which in turn undergoes cleavage at the benzylic C—O bond to generatethe phosphoric acid and the quinone methide intermediate. Examples ofthis class of prodrugs are described by Mitchell et al. (1992) J. Chem.Soc. Perkin Trans. II 2345; Glazier WO 91/19721. Still other benzylicprodrugs have been described containing a carboxylic ester-containinggroup attached to the benzylic methylene (Glazier WO 91/19721).Thio-containing prodrugs are reported to be useful for the intracellulardelivery of phosphonate drugs. These proesters contain an ethylthiogroup in which the thiol group is either esterified with an acyl groupor combined with another thiol group to form a disulfide.Deesterification or reduction of the disulfide generates the free thiointermediate which subsequently breaks down to the phosphoric acid andepisulfide (Puech et al. (1993) Antiviral Res., 22: 155-174; Benzaria etal. (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate esters have alsobeen described as prodrugs of phosphorus-containing compounds (Erion etal., U.S. Pat. No. 6,312,662).

“Protecting group” refers to a moiety of a compound that masks or altersthe properties of a functional group or the properties of the compoundas a whole. Chemical protecting groups and strategies forprotection/deprotection are well known in the art. See e.g., ProtectiveGroups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons,Inc., New York, 1991. Protecting groups are often utilized to mask thereactivity of certain functional groups, to assist in the efficiency ofdesired chemical reactions, e.g., making and breaking chemical bonds inan ordered and planned fashion. Protection of functional groups of acompound alters other physical properties besides the reactivity of theprotected functional group, such as the polarity, lipophilicity(hydrophobicity), and other properties which can be measured by commonanalytical tools. Chemically protected intermediates may themselves bebiologically active or inactive.

Protected compounds may also exhibit altered, and in some cases,optimized properties in vitro and in vivo, such as passage throughcellular membranes and resistance to enzymatic degradation orsequestration. In this role, protected compounds with intendedtherapeutic effects may be referred to as prodrugs. Another function ofa protecting group is to convert the parental drug into a prodrug,whereby the parental drug is released upon conversion of the prodrug invivo. Because active prodrugs may be absorbed more effectively than theparental drug, prodrugs may possess greater potency in vivo than theparental drug. Protecting groups are removed either in vitro, in theinstance of chemical intermediates, or in vivo, in the case of prodrugs.With chemical intermediates, it is not particularly important that theresulting products after deprotection, e.g., alcohols, bephysiologically acceptable, although in general it is more desirable ifthe products are pharmacologically innocuous.

Any reference to any of the compounds of the invention also includes areference to a physiologically acceptable salt thereof. Examples ofphysiologically acceptable salts of the compounds of the inventioninclude salts derived from an appropriate base, such as an alkali metal(for example, sodium), an alkaline earth (for example, magnesium),ammonium and NX₄ ⁺ (wherein X is C₁-C₄ alkyl). Physiologicallyacceptable salts of an hydrogen atom or an amino group include salts oforganic carboxylic acids such as acetic, benzoic, lactic, fumaric,tartaric, maleic, malonic, malic, isethionic, lactobionic and succinicacids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic,benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, suchas hydrochloric, sulfuric, phosphoric and sulfamic acids.Physiologically acceptable salts of a compound of an hydroxy groupinclude the anion of said compound in combination with a suitable cationsuch as Na⁺ and NX₄ ⁺ (wherein X is independently selected from H or aC₁-C₄ alkyl group).

For therapeutic use, salts of active ingredients of the compounds of theinvention will be physiologically acceptable, i.e. they will be saltsderived from a physiologically acceptable acid or base. However, saltsof acids or bases which are not physiologically acceptable may also finduse, for example, in the preparation or purification of aphysiologically acceptable compound. All salts, whether or not derivedform a physiologically acceptable acid or base, are within the scope ofthe present invention.

“Alkyl” is C₁-C₁₈ hydrocarbon containing normal, secondary, tertiary orcyclic carbon atoms. Examples are methyl (Me, —CH₃), ethyl (Et,—CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr,i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃.

“Alkenyl” is C₂-C₁₈ hydrocarbon containing normal, secondary, tertiaryor cyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp² double bond. Examples include, but are not limitedto, ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), cyclopentenyl(—C₅H₇), and 5-hexenyl (—CH₂ CH₂CH₂CH₂CH═CH₂).

“Alkynyl” is C₂-C₁₈ hydrocarbon containing normal, secondary, tertiaryor cyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp triple bond. Examples include, but are not limited to,acetylenic (—C≡CH) and propargyl (—CH₂C≡CH),

“Alkylene” refers to a saturated, branched or straight chain or cyclichydrocarbon radical of 1-18 carbon atoms, and having two monovalentradical centers derived by the removal of two hydrogen atoms from thesame or two different carbon atoms of a parent alkane. Typical alkyleneradicals include, but are not limited to, methylene (—CH₂—) 1,2-ethyl(—CH₂CH₂—), 1,3-propyl (—CH₂CH₂CH₂—), 1,4-butyl (—CH₂CH₂CH₂CH₂—), andthe like.

“Alkenylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical of 2-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or two different carbon atoms of a parent alkene. Typicalalkenylene radicals include, but are not limited to, 1,2-ethylene(—CH═CH—).

“Alkynylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical of 2-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or two different carbon atoms of a parent alkyne. Typicalalkynylene radicals include, but are not limited to, acetylene (—C≡C—),propargyl (—CH₂C≡C—), and 4-pentynyl (—CH₂CH₂CH₂C≡CH—).

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-20 carbonatoms derived by the removal of one hydrogen atom from a single carbonatom of a parent aromatic ring system. Typical aryl groups include, butare not limited to, radicals derived from benzene, substituted benzene,naphthalene, anthracene, biphenyl, and the like.

“Arylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. The arylalkyl group comprises 6to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl, alkenylor alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and thearyl moiety is 5 to 14 carbon atoms.

“Substituted alkyl”, “substituted aryl”, and “substituted arylalkyl”mean alkyl, aryl, and arylalkyl respectively, in which one or morehydrogen atoms are each independently replaced with a non-hydrogensubstituent. Typical substituents include, but are not limited to, —X,—R, —O⁻, —OR, —SR, —S⁻, —NR₂, —NR₃, ═NR, —CX₃, —CN, —OCN, —SCN, —N═C═O,—NCS, —NO, —NO₂, ═N₂, —N₃, NC(═O)R, —C(═O)R, —C(═O)NRR—S(═O)₂O—,—S(═O)₂OH, —S(═O)₂R, —OS(═O)₂OR, —S(═O)₂NR, —S(═O)R, —OP(═O)O₂R,—P(═O)O₂RRR—P(═O)(O⁻)₂, —P(═O)(OH)₂, —C(═O)R, —C(═O)X, —C(S)R, —C(O)OR,—C(O)O⁻, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NRR, —C(S)NRR, —C(NR)NRR, whereeach X is independently a halogen: F, Cl, Br, or I; and each R isindependently —H, alkyl, aryl, heterocycle, protecting group or prodrugmoiety. Alkylene, alkenylene, and alkynylene groups may also besimilarly substituted.

“Heterocycle” as used herein includes by way of example and notlimitation these heterocycles described in Paquette, Leo A.; Principlesof Modern Heterocyclic Chemistry (W. A. Benjamin, New York, 1968),particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry ofHeterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, NewYork, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28;and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment of theinvention “heterocycle” includes a “carbocycle” as defined herein,wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replacedwith a heteroatom (e.g. O, N, or S).

Examples of heterocycles include by way of example and not limitationpyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl,tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl,azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,isatinoyl, and bis-tetrahydrofuranyl:

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline. Still more typically, nitrogen bondedheterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl, and 1-piperidinyl.

“Carbocycle” refers to a saturated, unsaturated or aromatic ring having3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle,and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycleshave 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicycliccarbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5],[5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as abicyclo [5,6] or [6,6] system. Examples of monocyclic carbocyclesinclude cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and naphthyl.

“Linker” or “link” refers to a chemical moiety comprising a covalentbond or a chain or group of atoms that covalently attaches a phosphonategroup to a drug. Linkers include portions of substituents A¹ and A³,which include moieties such as: repeating units of alkyloxy (e.g.,polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g.,polyethyleneamino, Jeffamine™); and diacid ester and amides includingsuccinate, succinamide, diglycolate, malonate, and caproamide.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

The term “treatment” or “treating,” to the extent it relates to adisease or condition includes preventing the disease or condition fromoccurring, inhibiting the disease or condition, eliminating the diseaseor condition, and/or relieving one or more symptoms of the disease orcondition.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L or R and Sare used to denote the absolute configuration of the molecule about itschiral center(s). The prefixes d and l or (+) and (−) are employed todesignate the sign of rotation of plane-polarized light by the compound,with (−) or l meaning that the compound is levorotatory. A compoundprefixed with (+) or d is dextrorotatory. For a given chemicalstructure, these stereoisomers are identical except that they are mirrorimages of one another. A specific stereoisomer may also be referred toas an enantiomer, and a mixture of such isomers is often called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.The terms “racemic mixture” and “racemate” refer to an equimolar mixtureof two enantiomeric species, devoid of optical activity.

Protecting Groups

In the context of the present invention, protecting groups includeprodrug moieties and chemical protecting groups.

Protecting groups are available, commonly known and used, and areoptionally used to prevent side reactions with the protected groupduring synthetic procedures, i.e. routes or methods to prepare thecompounds of the invention. For the most part the decision as to whichgroups to protect, when to do so, and the nature of the chemicalprotecting group “PG” will be dependent upon the chemistry of thereaction to be protected against (e.g., acidic, basic, oxidative,reductive or other conditions) and the intended direction of thesynthesis. The PG groups do not need to be, and generally are not, thesame if the compound is substituted with multiple PG. In general, PGwill be used to protect functional groups such as carboxyl, hydroxyl,thio, or amino groups and to thus prevent side reactions or to otherwisefacilitate the synthetic efficiency. The order of deprotection to yieldfree, deprotected groups is dependent upon the intended direction of thesynthesis and the reaction conditions to be encountered, and may occurin any order as determined by the artisan.

Various functional groups of the compounds of the invention may beprotected. For example, protecting groups for —OH groups (whetherhydroxyl, carboxylic acid, phosphonic acid, or other functions) include“ether- or ester-forming groups”. Ether- or ester-forming groups arecapable of functioning as chemical protecting groups in the syntheticschemes set forth herein. However, some hydroxyl and thio protectinggroups are neither ether-nor ester-forming groups, as will be understoodby those skilled in the art, and are included with amides, discussedbelow.

A very large number of hydroxyl protecting groups and amide-forminggroups and corresponding chemical cleavage reactions are described inProtective Groups in Organic Synthesis, Theodora W. Greene (John Wiley &Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (“Greene”). See alsoKocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart,N.Y., 1994), which is incorporated by reference in its entirety herein.In particular Chapter 1, Protecting Groups: An Overview, pages 1-20,Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, DiolProtecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting Groups,pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184. Forprotecting groups for carboxylic acid, phosphonic acid, phosphonate,sulfonic acid and other protecting groups for acids see Greene as setforth below. Such groups include by way of example and not limitation,esters, amides, hydrazides, and the like.

Ether- and Ester-Forming Protecting Groups

Ester-forming groups include: (1) phosphonate ester-forming groups, suchas phosphonamidate esters, phosphorothioate esters, phosphonate esters,and phosphon-bis-amidates; (2) carboxyl ester-forming groups, and (3)sulphur ester-forming groups, such as sulphonate, sulfate, andsulfinate.

The phosphonate moieties of the compounds of the invention may or maynot be prodrug moieties, i.e. they may or may not be susceptible tohydrolytic or enzymatic cleavage or modification. Certain phosphonatemoieties are stable under most or nearly all metabolic conditions. Forexample, a dialkylphosphonate, where the alkyl groups are two or morecarbons, may have appreciable stability in vivo due to a slow rate ofhydrolysis.

Within the context of phosphonate prodrug moieties, a large number ofstructurally-diverse prodrugs have been described for phosphonic acids(Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997))and are included within the scope of the present invention. An exemplaryphosphonate ester-forming group is the phenyl carbocycle in substructureA₃ having the formula:

wherein R₁ may be H or C₁-C₁₂ alkyl; m1 is 1, 2, 3, 4, 5, 6, 7 or 8, andthe phenyl carbocycle is substituted with 0 to 3 R₂ groups. Where Y₁ isO, a lactate ester is formed, and where Y₁ is N(R₂), N(OR₂) or N(N(R₂)₂,a phosphonamidate ester results.

In its ester-forming role, a protecting group typically is bound to anyacidic group such as, by way of example and not limitation, a —CO₂H or—C(S)OH group, thereby resulting in —CO₂R^(x) where R^(x) is definedherein. Also, R^(x) for example includes the enumerated ester groups ofWO 95/07920.

Examples of protecting groups include:

C₃-C₁₂ heterocycle (described above) or aryl. These aromatic groupsoptionally are polycyclic or monocyclic. Examples include phenyl,spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4-and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and5-isothiazolyl, 3- and 4-pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-,2-, 4- and 5-pyrimidinyl,

C₃-C₁₂ heterocycle or aryl substituted with halo, R¹, R¹—O—C₁-C₁₂alkylene, C₁-C₁₂ alkoxy, CN, NO₂, OH, carboxy, carboxyester, thiol,thioester, C₁-C₁₂ haloalkyl (1-6 halogen atoms), C₂-C₁₂ alkenyl orC₂-C₁₂ alkynyl. Such groups include 2-, 3- and 4-alkoxyphenyl (C₁-C₁₂alkyl), 2-, 3- and 4-methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-,2,4-, 2,5-, 2,6-, 3,4- and 3,5-diethoxyphenyl, 2- and3-carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-4-hydroxyphenyl, 2- and3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6-hydroxyphenyl, 2-, 3- and4-O-acetylphenyl, 2-, 3- and 4-dimethylaminophenyl, 2-, 3- and4-methylmercaptophenyl, 2-, 3- and 4-halophenyl (including 2-, 3- and4-fluorophenyl and 2-, 3- and 4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-,3,4- and 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and3,5-biscarboxyethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dihalophenyl(including 2,4-difluorophenyl and 3,5-difluorophenyl), 2-, 3- and4-haloalkylphenyl (1 to 5 halogen atoms, C₁-C₁₂ alkyl including4-trifluoromethylphenyl), 2-, 3- and 4-cyanophenyl, 2-, 3- and4-nitrophenyl, 2-, 3- and 4-haloalkylbenzyl (1 to 5 halogen atoms,C₁-C₁₂ alkyl including 4-trifluoromethylbenzyl and 2-, 3- and4-trichloromethylphenyl and 2-, 3- and 4-trichloromethylphenyl),4-N-methylpiperidinyl, 3-N-methylpiperidinyl, 1-ethylpiperazinyl,benzyl, alkylsalicylphenyl (C₁-C₄ alkyl, including 2-, 3- and4-ethylsalicylphenyl), 2-, 3- and 4-acetylphenyl, 1,8-dihydroxynaphthyl(—C₁₀H₆—OH) and aryloxy ethyl [C₆-C₈ aryl (including phenoxy ethyl)],2,2′-dihydroxybiphenyl, 2-, 3- and 4-N,N-dialkylaminophenol,—C₆H₄CH₂—N(CH₃)₂, trimethoxybenzyl, triethoxybenzyl, 2-alkyl pyridinyl(C₁₋₄ alkyl);

esters of 2-carboxyphenyl; and C₁-C₄ alkylene-C₃-C₆ aryl (includingbenzyl, —CH₂-pyrrolyl, —CH₂-thienyl, —CH₂-imidazolyl, —CH₂-oxazolyl,—CH₂-isoxazolyl, —CH₂-thiazolyl, —CH₂-isothiazolyl, —CH₂-pyrazolyl,—CH₂-pyridinyl and —CH₂-pyrimidinyl) substituted in the aryl moiety by 3to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen,C₁-C₁₂ alkoxy (including methoxy and ethoxy), cyano, nitro, OH, C₁-C₁₂haloalkyl (1 to 6 halogen atoms; including —CH₂CCl₃), C₁-C₁₂ alkyl(including methyl and ethyl), C₂-C₁₂ alkenyl or C₂-C₁₂ alkynyl; alkoxyethyl [C₁-C₆ alkyl including —CH₂—CH₂—O—CH₃ (methoxy ethyl)]; alkylsubstituted by any of the groups set forth above for aryl, in particularOH or by 1 to 3 halo atoms (including —CH₃, —CH(CH₃)₂, —C(CH₃)₃,—CH₂CH₃, —(CH₂)₂CH₃, —(CH₂)₃CH₃, —(CH₂)₄CH₃, —(CH₂)₅CH₃, —CH₂CH₂F,—CH₂CH₂Cl, —CH₂CF₃, and —CH₂CCl₃);

propylmorpholino, 2,3-dihydro-6-hydroxyindene, sesamol, catecholmonoester, —CH₂—C(O)—N(R¹)₂, —CH₂—S(O)(R¹), —CH₂—S(O)₂(R¹),—CH₂—CH(OC(O)CH₂R¹)—CH₂(OC(O)CH₂R¹), cholesteryl, enolpyruvate(HOOC—C(═CH₂)—), glycerol;

a 5 or 6 carbon monosaccharide, disaccharide or oligosaccharide (3 to 9monosaccharide residues);

triglycerides such as α-D-β-diglycerides (wherein the fatty acidscomposing glyceride lipids generally are naturally occurring saturatedor unsaturated C₆₋₂₆, C₆₋₁₈ or C₆₋₁₀ fatty acids such as linoleic,lauric, myristic, palmitic, stearic, oleic, palmitoleic, linolenic andthe like fatty acids) linked to acyl of the parental compounds hereinthrough a glyceryl oxygen of the triglyceride;

phospholipids linked to the carboxyl group through the phosphate of thephospholipid;

phthalidyl (shown in FIG. 1 of Clayton et al., Antimicrob. Agents Chemo.(1974) 5(6):670-671);

cyclic carbonates such as (5-R_(d)-2-oxo-1,3-dioxolen-4-yl)methyl esters(Sakamoto et al., Chem. Pharm. Bull. (1984) 32(6)2241-2248) where R_(d)is R₁, R₄ or aryl; and

The hydroxyl groups of the compounds of this invention optionally aresubstituted with one of groups III, IV or V disclosed in WO 94/21604, orwith isopropyl.

Table A lists examples of protecting group ester moieties that forexample can be bonded via oxygen to —C(O)O— and —P(O)(O—)₂ groups.Several amidates also are shown, which are bound directly to —C(O)— or—P(O)₂. Esters of structures 1-5, 8-10 and 16, 17, 19-22 are synthesizedby reacting the compound herein having a free hydroxyl with thecorresponding halide (chloride or acyl chloride and the like) andN,N-dicyclohexyl-N-morpholine carboxamidine (or another base such asDBU, triethylamine, CsCO₃, N,N-dimethylaniline and the like) in DMF (orother solvent such as acetonitrile or N-methylpyrrolidone). When thecompound to be protected is a phosphonate, the esters of structures 5-7,11, 12, 21, and 23-26 are synthesized by reaction of the alcohol oralkoxide salt (or the corresponding amines in the case of compounds suchas 13, 14 and 15) with the monochlorophosphonate or dichlorophosphonate(or another activated phosphonate).

TABLE A  1. —CH₂—C(O)—N(R₁)₂*  2. —CH₂—S(O)(R₁)  3. —CH₂—S(O)₂(R₁)  4.—CH₂—O—C(O)—CH₂—C₆H₅  5. 3-cholesteryl  6. 3-pyridyl  7.N-ethylmorpholino  8. —CH₂—O—C(O)—C₆H₅  9. —CH₂—O—C(O)—CH₂CH₃ 10.—CH₂—O—C(O)—C(CH₃)₃ 11. —CH₂—CCl₃ 12. —C₆H₅ 13. —NH—CH₂—C(O)O—CH₂CH₃ 14.—N(CH₃)—CH₂—C(O)O—CH₂CH₃ 15. —NHR₁ 16. —CH₂—O—C(O)—C₁₀H₁₅ 17.—CH₂—O—C(O)—CH(CH₃)₂ 18. —CH₂—C*H(OC(O)CH₂R₁)—CH₂—(OC(O)CH₂R₁)* 19.

20.

21.

22.

23.

24.

25.

26.

#-chiral center is (R), (S) or racemate.

Other esters that are suitable for use herein are described in EP632048.

Protecting groups also includes “double ester” formingprofunctionalities such as —CH₂OC(O)OCH₃,

—CH₂SCOCH₃, —CH₂OCON(CH₃)₂, or alkyl- or aryl-acyloxyalkyl groups of thestructure —CH(R¹ or W⁵)O((CO)R³⁷) or —CH(R¹ or W⁵)((CO)OR³⁸) (linked tooxygen of the acidic group) wherein R³⁷ and R³⁸ are alkyl, aryl, oralkylaryl groups (see U.S. Pat. No. 4,968,788). Frequently R³⁷ and R³⁸are bulky groups such as branched alkyl, ortho-substituted aryl,meta-substituted aryl, or combinations thereof, including normal,secondary, iso- and tertiary alkyls of 1-6 carbon atoms. An example isthe pivaloyloxymethyl group. These are of particular use with prodrugsfor oral administration. Examples of such useful protecting groups arealkylacyloxymethyl esters and their derivatives, including—CH(CH₂CH₂OCH₃)OC(O)C(CH₃)₃,

CH₂OC(O)C₁₀H₁₅, —CH₂OC(O)C(CH₃)₃, —CH(CH₂OCH₃)OC(O)C(CH₃)₃,—CH(CH(CH₃)₂)OC(O)C(CH₃)₃, —CH₂OC(O)CH₂CH(CH₃)₂, —CH₂OC(O)C₆H₁₁,—CH₂OC(O)C₆H₅, —CH₂OC(O)C₁₀H₁₅, —CH₂OC(O)CH₂CH₃, —CH₂OC(O)CH(CH₃)₂,—CH₂OC(O)C(CH₃)₃ and —CH₂OC(O)CH₂C₆H₅.

In some claims the protected acidic group is an ester of the acidicgroup and is the residue of a hydroxyl-containing functionality. Inother claims, an amino compound is used to protect the acidfunctionality. The residues of suitable hydroxyl or amino-containingfunctionalities are set forth above or are found in WO 95/07920. Ofparticular interest are the residues of amino acids, amino acid esters,polypeptides, or aryl alcohols. Typical amino acid, polypeptide andcarboxyl-esterified amino acid residues are described on pages 11-18 andrelated text of WO 95/07920 as groups L1 or L2. WO 95/07920 expresslyteaches the amidates of phosphonic acids, but it will be understood thatsuch amidates are formed with any of the acid groups set forth hereinand the amino acid residues set forth in WO 95/07920.

Typical esters for protecting acidic functionalities are also describedin WO 95/07920, again understanding that the same esters can be formedwith the acidic groups herein as with the phosphonate of the '920publication. Typical ester groups are defined at least on WO 95/07920pages 89-93 (under R³¹ or R³⁵), the table on page 105, and pages 21-23(as R). Of particular interest are esters of unsubstituted aryl such asphenyl or arylalkyl such benzyl, or hydroxy-, halo-, alkoxy-, carboxy-and/or alkylestercarboxy-substituted aryl or alkylaryl, especiallyphenyl, ortho-ethoxyphenyl, or C₁-C₄ alkylestercarboxyphenyl (salicylateC₁-C₁₂ alkylesters).

The protected acidic groups, particularly when using the esters oramides of WO 95/07920, are useful as prodrugs for oral administration.However, it is not essential that the acidic group be protected in orderfor the compounds of this invention to be effectively administered bythe oral route. When the compounds of the invention having protectedgroups, in particular amino acid amidates or substituted andunsubstituted aryl esters are administered systemically or orally theyare capable of hydrolytic cleavage in vivo to yield the free acid.

One or more of the acidic hydroxyls are protected. If more than oneacidic hydroxyl is protected then the same or a different protectinggroup is employed, e.g., the esters may be different or the same, or amixed amidate and ester may be used.

Typical hydroxy protecting groups described in Greene (pages 14-118)include substituted methyl and alkyl ethers, substituted benzyl ethers,silyl ethers, esters including sulfonic acid esters, and carbonates. Forexample:

-   -   Ethers (methyl, t-butyl, allyl);    -   Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl,        t-Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl,        Benzyloxymethyl, p-Methoxybenzyloxymethyl,        (4-Methoxyphenoxy)methyl, Guaiacolmethyl, t-Butoxymethyl,        4-Pentenyloxymethyl, Siloxymethyl, 2-Methoxyethoxymethyl,        2,2,2-Trichloroethoxymethyl, Bis(2-chloroethoxy)methyl,        2-(Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl,        3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl,        1-Methoxycyclohexyl, 4-Methoxytetrahydropyranyl,        4-Methoxytetrahydrothiopyranyl, 4-Methoxytetrahydropthiopyranyl        S,S-Dioxido,        1-[(2-Chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,        1,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl,        2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl));    -   Substituted Ethyl Ethers (1-Ethoxyethyl,        1-(2-Chloroethoxy)ethyl, 1-Methyl-1-methoxyethyl,        1-Methyl-1-benzyloxyethyl, 1-Methyl-1-benzyloxy-2-fluoroethyl,        2,2,2-Trichloroethyl, 2-Trimethylsilylethyl,        2-(Phenylselenyl)ethyl,    -   p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl);    -   Substituted Benzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl,        o-Nitrobenzyl, p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl,        p-Cyanobenzyl, p-Phenylbenzyl, 2- and 4-Picolyl,        3-Methyl-2-picolyl N-Oxido, Diphenylmethyl,        p,p′-Dinitrobenzhydryl, 5-Dibenzosuberyl, Triphenylmethyl,        α-Naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,        Di(p-methoxyphenyl)phenylmethyl, Tri(p-methoxyphenyl)methyl,        4-(4′-Bromophenacyloxy)phenyldiphenylmethyl,        4,4′,4″-Tris(4,5-dichlorophthalimidophenyl)methyl,        4,4′,4″-Tris(levulinoyloxyphenyl)methyl,        4,4′,4″-Tris(benzoyloxyphenyl)methyl,        3-(Imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,        1,1-Bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-Anthryl,        9-(9-Phenyl)xanthenyl, 9-(9-Phenyl-10-oxo)anthryl,        1,3-Benzodithiolan-2-yl, Benzisothiazolyl S,S-Dioxido);    -   Silyl Ethers (Trimethylsilyl, Triethylsilyl, Triisopropylsilyl,        Dimethylisopropylsilyl, Diethylisopropylsilyl,        Dimethylthexylsilyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl,        Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl,        Diphenylmethylsilyl, t-Butylmethoxyphenylsilyl);    -   Esters (Formate, Benzoylformate, Acetate, Choroacetate,        Dichloroacetate, Trichloroacetate, Trifluoroacetate,        Methoxyacetate, Triphenylmethoxyacetate, Phenoxyacetate,        p-Chlorophenoxyacetate, p-poly-Phenylacetate,        3-Phenylpropionate, 4-Oxopentanoate (Levulinate),        4,4-(Ethylenedithio)pentanoate, Pivaloate, Adamantoate,        Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate,        2,4,6-Trimethylbenzoate (Mesitoate));    -   Carbonates (Methyl, 9-Fluorenylmethyl, Ethyl,        2,2,2-Trichloroethyl, 2-(Trimethylsilyl)ethyl,        2-(Phenylsulfonyl)ethyl, 2-(Triphenylphosphonio)ethyl, Isobutyl,        Vinyl, Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl,        3,4-Dimethoxybenzyl, o-Nitrobenzyl, p-Nitrobenzyl, S-Benzyl        Thiocarbonate, 4-Ethoxy-1-naphthyl, Methyl Dithiocarbonate);    -   Groups With Assisted Cleavage (2-Iodobenzoate, 4-Azidobutyrate,        4-Nitro-4-methylpentanoate, o-(Dibromomethyl)benzoate,        2-Formylbenzenesulfonate, 2-(Methylthiomethoxy)ethyl Carbonate,        4-(Methylthiomethoxy)butyrate,        2-(Methylthiomethoxymethyl)benzoate); Miscellaneous Esters        (2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro-4-(1,1,3,3        tetramethylbutyl)phenoxyacetate,        2,4-Bis(1,1-dimethylpropyl)phenoxyacetate,        Chlorodiphenylacetate, Isobutyrate, Monosuccinate,        (E)-2-Methyl-2-butenoate (Tigloate),        o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, α-Naphthoate,        Nitrate, Alkyl N,N,N′,N′-Tetramethylphosphorodiamidate,        N-Phenylcarbamate, Borate, Dimethylphosphinothioyl,        2,4-Dinitrophenylsulfenate); and    -   Sulfonates (Sulfate, Methanesulfonate (Mesylate),        Benzylsulfonate, Tosylate).

Typical 1,2-diol protecting groups (thus, generally where two OH groupsare taken together with the protecting functionality) are described inGreene at pages 118-142 and include Cyclic Acetals and Ketals(Methylene, Ethylidene, 1-t-Butylethylidene, 1-Phenylethylidene,(4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide(Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene,Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene,3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters(Methoxymethylene, Ethoxymethylene, Dimethoxymethylene,1-Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene,α-Methoxybenzylidene, 1-(N,N-Dimethylamino)ethylidene Derivative,α-(N,N-Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene);Silyl Derivatives (Di-t-butylsilylene Group,1,3-(1,1,3,3-Tetraisopropyldisiloxanylidene), andTetra-t-butoxydisiloxane-1,3-diylidene), Cyclic Carbonates, CyclicBoronates, Ethyl Boronate and Phenyl Boronate.

More typically, 1,2-diol protecting groups include those shown in TableB, still more typically, epoxides, acetonides, cyclic ketals and arylacetals.

TABLE B

wherein R⁹ is C₁-C₆ alkyl.

Amino Protecting Groups

Another set of protecting groups include any of the typical aminoprotecting groups described by Greene at pages 315-385. They include:

-   -   Carbamates: (methyl and ethyl, 9-fluorenylmethyl,        9(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl,        2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,        4-methoxyphenacyl);    -   Substituted Ethyl: (2,2,2-trichoroethyl, 2-trimethylsilylethyl,        2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,        1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,        1,1-dimethyl-2,2,2-trichloroethyl,        1-methyl-1-(4-biphenylyl)ethyl,        1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2′- and        4′-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl,        1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl,        4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio,        benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl,        p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl,        9-anthrylmethyl, diphenylmethyl);    -   Groups With Assisted Cleavage: (2-methylthioethyl,        2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,        [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl,        2,4-dimethylthiophenyl, 2-phosphonioethyl,        2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl,        m-choro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl,        5-benzisoxazolylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl);    -   Groups Capable of Photolytic Cleavage: (m-nitrophenyl,        3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl,        phenyl(o-nitrophenyl)methyl); Urea-Type Derivatives        (phenothiazinyl-(10)-carbonyl, N-p-toluenesulfonylaminocarbonyl,        N′-phenylaminothiocarbonyl);    -   Miscellaneous Carbamates: (t-amyl, S-benzyl thiocarbamate,        p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,        cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,        2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,        1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl,        1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl,        2-Iodoethyl, Isobornyl, Isobutyl, Isonicotinyl,        p-(p′-Methoxyphenylazo)benzyl, 1-methylcyclobutyl,        1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,        1-methyl-1-(3,5-dimethoxyphenyl)ethyl,        1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,        1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,        2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl,        2,4,6-trimethylbenzyl);    -   Amides: (N-formyl, N-acetyl, N-choroacetyl, N-trichoroacetyl,        N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl,        N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl,        N-benzoyl, N-p-phenylbenzoyl);    -   Amides With Assisted Cleavage: (N-o-nitrophenylacetyl,        N-o-nitrophenoxyacetyl, N-acetoacetyl,        (N′-dithiobenzyloxycarbonylamino)acetyl,        N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl,        N-2-methyl-2-(o-nitrophenoxy)propionyl,        N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,        N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl,        N-acetylmethionine, N-o-nitrobenzoyl,        N-o-(benzoyloxymethyl)benzoyl, 4,5-diphenyl-3-oxazolin-2-one);    -   Cyclic Imide Derivatives: (N-phthalimide, N-dithiasuccinoyl,        N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl,        N-1,1,4,4-tetramethyldisilylazacyclopentane adduct,        5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,        5-substituted 1,3-dibenzyl-1,3-5-triazacyclohexan-2-one,        1-substituted 3,5-dinitro-4-pyridonyl);    -   N-Alkyl and N-Aryl Amines: (N-methyl, N-allyl,        N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl,        N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), Quaternary        Ammonium Salts, N-benzyl, N-di(4-methoxyphenyl)methyl,        N-5-dibenzosuberyl, N-triphenylmethyl,        N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,        N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl,        N-2-picolylamine N′-oxide);    -   Imine Derivatives: (N-1,1-dimethylthiomethylene, N-benzylidene,        N-p-methoxybenzylidene, N-diphenylmethylene,        N-[(2-pyridyl)mesityl]methylene,        N,(N′,N′-dimethylaminomethylene, N,N-isopropylidene,        N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene,        N-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylidene);    -   Enamine Derivatives: (N-(5,5-dimethyl-3-oxo-1-cyclohexenyl));    -   N-Metal Derivatives (N-borane derivatives, N-diphenylborinic        acid derivatives, N-[phenyl(pentacarbonylchromium- or        -tungsten)]carbenzyl, N-copper or N-zinc chelate);    -   N—N Derivatives: (N-nitro, N-nitroso, N-oxide);    -   N—P Derivatives: (N-diphenylphosphinyl,        N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkyl        phosphoryl, N-dibenzyl phosphoryl, N-diphenyl phosphoryl);    -   N—Si Derivatives, N—S Derivatives, and N-Sulfenyl Derivatives:        (N-benzenesulfenyl, N-o-nitrobenzenesulfenyl,        N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl,        N-2-nitro-4-methoxybenzenesulfenyl, N-triphenylmethylsulfenyl,        N-3-nitropyridinesulfenyl); and N-sulfonyl Derivatives        (N-p-toluenesulfonyl, N-benzenesulfonyl,        N-2,3,6-trimethyl-4-methoxybenzenesulfonyl,        N-2,4,6-trimethoxybenzenesulfonyl,        N-2,6-dimethyl-4-methoxybenzenesulfonyl,        N-pentamethylbenzenesulfonyl,        N-2,3,5,6,-tetramethyl-4-methoxybenzenesulfonyl,        N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl,        N-2,6-dimethoxy-4-methylbenzenesulfonyl,        N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl,        N-β-trimethylsilyethanesulfonyl, N-9-anthracenesulfonyl,        N-4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonyl,        N-benzylsulfonyl, N-trifluoromethylsulfonyl,        N-phenacylsulfonyl).

More typically, protected amino groups include carbamates and amides,still more typically, —NHC(O)R¹ or —N═CR¹N(R¹)₂. Another protectinggroup, also useful as a prodrug for amino or —NH(R⁵), is:

See for example Alexander, J. et al. (1996) J. Med. Chem. 39:480-486.

Amino Acid and Polypeptide Protecting Group and Conjugates

An amino acid or polypeptide protecting group of a compound of theinvention has the structure R¹⁵NHCH(R¹⁶)C(O)—, where R¹⁵ is H, an aminoacid or polypeptide residue, or R⁵, and R¹⁶ is defined below.

R¹⁶ is lower alkyl or lower alkyl (C₁-C₆) substituted with amino,carboxyl, amide, carboxyl ester, hydroxyl, C₆-C₇ aryl, guanidinyl,imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate. R¹⁰also is taken together with the amino acid α N to form a proline residue(R¹⁰=—CH₂)₃—). However, R¹⁰ is generally the side group of anaturally-occurring amino acid such as H, —CH₃, —CH(CH₃)₂,—CH₂—CH(CH₃)₂, —CHCH₃—CH₂—CH₃, —CH₂—C₆H₅, —CH₂CH₂—S—CH₃, —CH₂OH,—CH(OH)—CH₃, —CH₂—SH, —CH₂—C₆H₄OH, —CH₂—CO—NH₂, —CH₂—CH₂—CO—NH₂,—CH₂—COOH, —CH₂—CH₂—COOH, —(CH₂)₄—NH₂ and —(CH₂)₃—NH—C(NH₂)—NH₂. R₁₀also includes 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl,imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.

Another set of protecting groups include the residue of anamino-containing compound, in particular an amino acid, a polypeptide, aprotecting group, —NHSO₂R, NHC(O)R, —N(R)₂, NH₂ or —NH(R)(H), wherebyfor example a carboxylic acid is reacted, i.e. coupled, with the amineto form an amide, as in C(O)NR₂. A phosphonic acid may be reacted withthe amine to form a phosphonamidate, as in —P(O)(OR)(NR₂).

In general, amino acids have the structure R¹⁷C(O)CH(R¹⁶)NH—, where R¹⁷is —OH, —OR, an amino acid or a polypeptide residue. Amino acids are lowmolecular weight compounds, on the order of less than about 1000 MW andwhich contain at least one amino or imino group and at least onecarboxyl group. Generally the amino acids will be found in nature, i.e.,can be detected in biological material such as bacteria or othermicrobes, plants, animals or man. Suitable amino acids typically arealpha amino acids, i.e. compounds characterized by one amino or iminonitrogen atom separated from the carbon atom of one carboxyl group by asingle substituted or unsubstituted alpha carbon atom. Of particularinterest are hydrophobic residues such as mono- or di-alkyl or arylamino acids, cycloalkylamino acids and the like. These residuescontribute to cell permeability by increasing the partition coefficientof the parental drug. Typically, the residue does not contain asulfhydryl or guanidino substituent.

Naturally-occurring amino acid residues are those residues foundnaturally in plants, animals or microbes, especially proteins thereof.Polypeptides most typically will be substantially composed of suchnaturally-occurring amino acid residues. These amino acids are glycine,alanine, valine, leucine, isoleucine, serine, threonine, cysteine,methionine, glutamic acid, aspartic acid, lysine, hydroxylysine,arginine, histidine, phenylalanine, tyrosine, tryptophan, proline,asparagine, glutamine and hydroxyproline. Additionally, unnatural aminoacids, for example, valanine, phenylglycine and homoarginine are alsoincluded. Commonly encountered amino acids that are not gene-encoded mayalso be used in the present invention. All of the amino acids used inthe present invention may be either the D- or L-optical isomer. Inaddition, other peptidomimetics are also useful in the presentinvention. For a general review, see Spatola, A. F., in Chemistry andBiochemistry of Amino Acids, Peptides and Proteins, B. Weinstein, eds.,Marcel Dekker, New York, p. 267 (1983).

When protecting groups are single amino acid residues or polypeptidesthey optionally are substituted at R³ of substituents A¹, A² or A³ inFormula I. These conjugates are produced by forming an amide bondbetween a carboxyl group of the amino acid (or C-terminal amino acid ofa polypeptide for example). Similarly, conjugates are formed between R³(Formula I) and an amino group of an amino acid or polypeptide.Generally, only one of any site in the parental molecule is amidatedwith an amino acid as described herein, although it is within the scopeof this invention to introduce amino acids at more than one permittedsite. Usually, a carboxyl group of R³ is amidated with an amino acid. Ingeneral, the α-amino or α-carboxyl group of the amino acid or theterminal amino or carboxyl group of a polypeptide are bonded to theparental functionalities, i.e., carboxyl or amino groups in the aminoacid side chains generally are not used to form the amide bonds with theparental compound (although these groups may need to be protected duringsynthesis of the conjugates as described further below).

With respect to the carboxyl-containing side chains of amino acids orpolypeptides it will be understood that the carboxyl group optionallywill be blocked, e.g., by R¹, esterified with R⁵ or amidated. Similarly,the amino side chains R¹⁶ optionally will be blocked with R¹ orsubstituted with R⁵.

Such ester or amide bonds with side chain amino or carboxyl groups, likethe esters or amides with the parental molecule, optionally arehydrolyzable in vivo or in vitro under acidic (pH<3) or basic (pH>10)conditions. Alternatively, they are substantially stable in thegastrointestinal tract of humans but are hydrolyzed enzymatically inblood or in intracellular environments. The esters or amino acid orpolypeptide amidates also are useful as intermediates for thepreparation of the parental molecule containing free amino or carboxylgroups. The free acid or base of the parental compound, for example, isreadily formed from the esters or amino acid or polypeptide conjugatesof this invention by conventional hydrolysis procedures.

When an amino acid residue contains one or more chiral centers, any ofthe D, L, meso, threo or erythro (as appropriate) racemates, scalematesor mixtures thereof may be used. In general, if the intermediates are tobe hydrolyzed non-enzymatically (as would be the case where the amidesare used as chemical intermediates for the free acids or free amines), Disomers are useful. On the other hand, L isomers are more versatilesince they can be susceptible to both non-enzymatic and enzymatichydrolysis, and are more efficiently transported by amino acid ordipeptidyl transport systems in the gastrointestinal tract.

Examples of suitable amino acids whose residues are represented by R^(x)or R^(y) include the following:

Glycine;

Aminopolycarboxylic acids, e.g., aspartic acid, β-hydroxyaspartic acid,glutamic acid, β-hydroxyglutamic acid, β-methylaspartic acid,β-methylglutamic acid, β,β-dimethylaspartic acid, γ-hydroxyglutamicacid, β,γ-dihydroxyglutamic acid, β-phenylglutamic acid,γ-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid,2-aminosuberic acid and 2-aminosebacic acid;

Amino acid amides such as glutamine and asparagine;

Polyamino- or polybasic-monocarboxylic acids such as arginine, lysine,β-aminoalanine, γ-aminobutyrine, ornithine, citruline, homoarginine,homocitrulline, hydroxylysine, allohydroxylsine and diaminobutyric acid;

Other basic amino acid residues such as histidine;

Diaminodicarboxylic acids such as α,α′-diaminosuccinic acid,α,α′-diaminoglutaric acid, α,α′-diaminoadipic acid, α,α′-diaminopimelicacid, α,α′-diamino-β-hydroxypimelic acid, α,α′-diaminosuberic acid,α,α′-diaminoazelaic acid, and α,α′-diaminosebacic acid;

Imino acids such as proline, hydroxyproline, allohydroxyproline,γ-methylproline, pipecolic acid, 5-hydroxypipecolic acid, andazetidine-2-carboxylic acid;

A mono- or di-alkyl (typically C₁-C₈ branched or normal) amino acid suchas alanine, valine, leucine, allylglycine, butyrine, norvaline,norleucine, heptyline, α-methylserine, α-amino-α-methyl-γ-hydroxyvalericacid, α-amino-α-methyl-δ-hydroxyvaleric acid,α-amino-α-methyl-ε-hydroxycaproic acid, isovaline, α-methylglutamicacid, α-aminoisobutyric acid, α-aminodiethylacetic acid,α-aminodiisopropylacetic acid, α-aminodi-n-propylacetic acid,α-aminodiisobutylacetic acid, α-aminodi-n-butylacetic acid,α-aminoethylisopropylacetic acid, α-amino-n-propylacetic acid,α-aminodiisoamyacetic acid, α-methylaspartic acid, α-methylglutamicacid, 1-aminocyclopropane-1-carboxylic acid, isoleucine, alloisoleucine,tert-leucine, α-methyltryptophan and α-amino-β-ethyl-β-phenylpropionicacid;

β-phenylserinyl;

Aliphatic α-amino-β-hydroxy acids such as serine, β-hydroxylcucine,β-hydroxynorleucine, β-hydroxynorvaline, and α-amino-β-hydroxystearicacid;

α-Amino, α-, γ-, δ- or ε-hydroxy acids such as homoserine,δ-hydroxynorvaline, γ-hydroxynorvaline and ε-hydroxynorleucine residues;canavine and canaline; γ-hydroxyornithine;

2-hexosaminic acids such as D-glucosaminic acid or D-galactosaminicacid;

α-Amino-β-thiols such as penicillamine, β-thiolnorvaline orβ-thiolbutyrine;

Other sulfur containing amino acid residues including cysteine;homocystine, β-phenylmethionine, methionine, S-allyl-L-cysteinesulfoxide, 2-thiolhistidine, cystathionine, and thiol ethers of cysteineor homocysteine;

Phenylalanine, tryptophan and ring-substituted α-amino acids such as thephenyl- or cyclohexylamino acids α-aminophenylacetic acid,α-aminocyclohexylacetic acid and α-amino-β-cyclohexylpropionic acid;phenylalanine analogues and derivatives comprising aryl, lower alkyl,hydroxy, guanidino, oxyalkylether, nitro, sulfur or halo-substitutedphenyl (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-,3,4-dichloro, o-, m- or p-methyl-, 2,4,6-trimethyl-, 2-ethoxy-5-nitro-,2-hydroxy-5-nitro- and p-nitro-phenylalanine); furyl-, thienyl-,pyridyl-, pyrimidinyl-, purinyl- or naphthyl-alanines; and tryptophananalogues and derivatives including kynurenine, 3-hydroxykynurenine,2-hydroxytryptophan and 4-carboxytryptophan;

α-Amino substituted amino acids including sarcosine (N-methylglycine),N-benzylglycine, N-methylalanine, N-benzylalanine,N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline andN-benzylvaline; and

α-Hydroxy and substituted α-hydroxy amino acids including serine,threonine, allothreonine, phosphoserine and phosphothreonine.

Polypeptides are polymers of amino acids in which a carboxyl group ofone amino acid monomer is bonded to an amino or imino group of the nextamino acid monomer by an amide bond. Polypeptides include dipeptides,low molecular weight polypeptides (about 1500-5000 MW) and proteins.Proteins optionally contain 3, 5, 10, 50, 75, 100 or more residues, andsuitably are substantially sequence-homologous with human, animal, plantor microbial proteins. They include enzymes (e.g., hydrogen peroxidase)as well as immunogens such as KLH, or antibodies or proteins of any typeagainst which one wishes to raise an immune response. The nature andidentity of the polypeptide may vary widely.

The polypeptide amidates are useful as immunogens in raising antibodiesagainst either the polypeptide (if it is not immunogenic in the animalto which it is administered) or against the epitopes on the remainder ofthe compound of this invention.

Antibodies capable of binding to the parental non-peptidyl compound areused to separate the parental compound from mixtures, for example indiagnosis or manufacturing of the parental compound. The conjugates ofparental compound and polypeptide generally are more immunogenic thanthe polypeptides in closely homologous animals, and therefore make thepolypeptide more immunogenic for facilitating raising antibodies againstit. Accordingly, the polypeptide or protein may not need to beimmunogenic in an animal typically used to raise antibodies, e.g.,rabbit, mouse, horse, or rat, but the final product conjugate should beimmunogenic in at least one of such animals. The polypeptide optionallycontains a peptidolytic enzyme cleavage site at the peptide bond betweenthe first and second residues adjacent to the acidic heteroatom. Suchcleavage sites are flanked by enzymatic recognition structures, e.g., aparticular sequence of residues recognized by a peptidolytic enzyme.

Peptidolytic enzymes for cleaving the polypeptide conjugates of thisinvention are well known, and in particular include carboxypeptidases.Carboxypeptidases digest polypeptides by removing C-terminal residues,and are specific in many instances for particular C-terminal sequences.Such enzymes and their substrate requirements in general are well known.For example, a dipeptide (having a given pair of residues and a freecarboxyl terminus) is covalently bonded through its α-amino group to thephosphorus or carbon atoms of the compounds herein. In claims where W₁is phosphonate it is expected that this peptide will be cleaved by theappropriate peptidolytic enzyme, leaving the carboxyl of the proximalamino acid residue to autocatalytically cleave the phosphonoamidatebond.

Suitable dipeptidyl groups (designated by their single letter code) areAA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW,AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS,RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF,NP, NS, NT, NR, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK,DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG, CH, CI,CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC, EE, EQ, EG,EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN, QD, QC, QE,QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, GD,GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV, HA, HR,HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT, HW, HY, HV,IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP, IS, IT, IW,IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM, LF, LP, LS,LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL, KK, KM, KF,KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI, ML, MK,MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, FI,FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE, PQ, PG,PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD, SC, SE,SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, TR, TN, TD,TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT, TW, TY, TV, WA, WR,WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT, WW, WY, WV,YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP, YS, YT, YW,YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS,VT, VW, VY and VV.

Tripeptide residues are also useful as protecting groups. When aphosphonate is to be protected, the sequence —X⁴-pro-X⁵— (where X⁴ isany amino acid residue and X⁵ is an amino acid residue, a carboxyl esterof proline, or hydrogen) will be cleaved by luminal carboxypeptidase toyield X⁴ with a free carboxyl, which in turn is expected toautocatalytically cleave the phosphonoamidate bond. The carboxy group ofX⁵ optionally is esterified with benzyl.

Dipeptide or tripeptide species can be selected on the basis of knowntransport properties and/or susceptibility to peptidases that can affecttransport to intestinal mucosal or other cell types. Dipeptides andtripeptides lacking an α-amino group are transport substrates for thepeptide transporter found in brush border membrane of intestinal mucosalcells (Bai, J. P. F., (1992) Pharm Res. 9:969-978). Transport competentpeptides can thus be used to enhance bioavailability of the amidatecompounds. Di- or tripeptides having one or more amino acids in the Dconfiguration are also compatible with peptide transport and can beutilized in the amidate compounds of this invention. Amino acids in theD configuration can be used to reduce the susceptibility of a di- ortripeptide to hydrolysis by proteases common to the brush border such asaminopeptidase N. In addition, di- or tripeptides alternatively areselected on the basis of their relative resistance to hydrolysis byproteases found in the lumen of the intestine. For example, tripeptidesor polypeptides lacking asp and/or glu are poor substrates foraminopeptidase A, di- or tripeptides lacking amino acid residues on theN-terminal side of hydrophobic amino acids (leu, tyr, phe, val, trp) arepoor substrates for endopeptidase, and peptides lacking a pro residue atthe penultimate position at a free carboxyl terminus are poor substratesfor carboxypeptidase P. Similar considerations can also be applied tothe selection of peptides that are either relatively resistant orrelatively susceptible to hydrolysis by cytosolic, renal, hepatic, serumor other peptidases. Such poorly cleaved polypeptide amidates areimmunogens or are useful for bonding to proteins in order to prepareimmunogens.

SPECIFIC EMBODIMENTS OF THE INVENTION

Specific values described for radicals, substituents, and ranges, aswell as specific embodiments of the invention described herein, are forillustration only; they do not exclude other defined values or othervalues within defined ranges.

In one specific embodiment of the invention, the conjugate is a compoundthat is substituted with one or more phosphonate groups either directlyor indirectly through a linker; and that is optionally substituted withone or more groups A⁰; or a pharmaceutically acceptable salt thereof,wherein:

A⁰ is A¹, A² or W³;

A¹ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, R¹, W³, a protecting group, or the formula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

and W^(5a) is a carbocycle or a heterocycle where W^(5a) isindependently substituted with 0 or 1 R² groups. A specific value forM12a is 1.

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

wherein W^(5a) is a carbocycle independently substituted with 0 or 1 R²groups;

In another specific embodiment of the invention A¹ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A¹ is of the formula:

wherein W^(5a) is a carbocycle independently substituted with 0 or 1 R²groups;

In another specific embodiment of the invention A¹ is of the formula:

wherein W^(5a) is a carbocycle or heterocycle where W^(5a) isindependently substituted with 0 or 1 R² groups.

In another specific embodiment of the invention A¹ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In a specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention M12b is 1.

In another specific embodiment of the invention M12b is 0, Y² is a bondand W⁵ is a carbocycle or heterocycle where W⁵ is optionally andindependently substituted with 1, 2, or 3 R² groups.

In another specific embodiment of the invention A² is of the formula:

wherein W^(5a) is a carbocycle or heterocycle where W^(5a) is optionallyand independently substituted with 1, 2, or 3 R² groups.

In another specific embodiment of the invention M12a is 1.

In another specific embodiment of the invention A² is selected fromphenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl andsubstituted pyridyl.

In another specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention M12b is 1.

In a specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R^(x)) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)).

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention M12d is 1.

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention W⁵ is a carbocycle.

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention W⁵ is phenyl.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R^(x)) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)).

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention R¹ is H.

In another specific embodiment of the invention A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R²) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); and Y^(2c) is O,N(R^(y)) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); Y^(2d) is O or N(R^(y));and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²).

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R²) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); and Y^(2c) is O,N(R^(y)) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); Y^(2d) is O or N(R^(y));and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²).

In another specific embodiment of the invention A³ is of the formula:

wherein: Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.

In another specific embodiment of the invention A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.

In another specific embodiment of the invention A³ is of the formula:

In a specific embodiment of the invention A⁰ is of the formula:

wherein each R is independently (C₁-C₆)alkyl.

In a specific embodiment of the invention R^(x) is independently H, R¹,W³, a protecting group, or the formula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

In a specific embodiment of the invention R^(x) is of the formula:

wherein Y^(1a) is O or S; and Y^(2c) is O, N(R^(y)) or S.

In a specific embodiment of the invention R^(x) is of the formula:

wherein Y^(1a) is O or S; and Y^(2d) is O or N(R^(y)).

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention R^(y) is hydrogen or alkyl of1 to 10 carbons.

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention Y¹ is O or S.

In a specific embodiment of the invention Y² is O, N(R^(y)) or S.

In one specific embodiment of the invention R^(x) is a group of theformula:

wherein:

m1a, m1b, m1c, m1d and m1e are independently 0 or 1;

m12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

R^(y) is H, W³, R² or a protecting group;

provided that:

if m1a, m12c, and m1d are 0, then m1b, m1c and m1e are 0;

if m1a and m12c are 0 and m1d is not 0, then m1b and m1c are 0;

if m1a and m1d are 0 and m12c is not 0, then m1b and at least one of m1cand m1e are 0;

if m1a is 0 and m12c and m1d are not 0, then m1b is 0;

if m12c and m1d are 0 and m1a is not 0, then at least two of m1b, m1cand m1e are 0;

if m12c is 0 and m1a and m1d are not 0, then at least one of m1b and m1care 0; and

if m1d is 0 and m1a and m12c are not 0, then at least one of m1c and m1eare 0.

In another specific embodiment, the invention provides a compound of theformula:

[DRUG]-(A⁰)_(nn)

or a pharmaceutically acceptable salt thereof wherein,

DRUG is a compound of any one of formulae 500-547;

nn is 1, 2, or 3;

A⁰ is A¹, A² or W³ with the proviso that the compound includes at leastone A¹;

A¹ is:

A² is:

A3 is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, R¹, W³, a protecting group, or the formula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3h), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is y;

R^(3c) is R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)((R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another embodiment, the invention provides a compound of any one offormulae 1-151 wherein:

A⁰ is A¹;

A¹ is

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R³, R^(3b), R^(3c) or R^(3d), provided that when R³ is bound to aheteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is —R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another specific embodiment, the invention provides a compound of theformula:

[DRUG]-[L-P(═Y¹)—Y²—R^(x)]_(nn)

or a pharmaceutically acceptable salt thereof wherein,

DRUG is a compound of any one of formulae 500-547;

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d)

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)),

—OC(Y¹)R^(x), —OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x),SC(Y¹)OR^(x), —SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x),—N(R^(x))C(Y¹)OR^(x), or —N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

M2 is 1, 2, or 3;

M1a, M1c, and M1d are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

nn is 1, 2, or 3; and

L is a linking group.

In another specific embodiment, the invention provides a compound ofwhich is a compound of the formula:

[DRUG]-(A⁰)_(nn)

or a pharmaceutically acceptable salt thereof wherein,

DRUG is a compound of any one of formulae 500-547;

nn is 1, 2, or 3;

A⁰ is A¹, A², or W³ with the proviso that the compound includes at leastone A¹;

A¹ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is y;

R^(3c) is R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)),

—OC(Y¹)R^(x), —OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x),—SC(Y¹)OR^(x), —SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x),—N(R^(x))C(Y¹)OR^(x), or —N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1e, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In compounds of the invention W⁵ carbocycles and W⁵ heterocycles may beindependently substituted with 0 to 3 R² groups. W⁵ may be a saturated,unsaturated or aromatic ring comprising a mono- or bicyclic carbocycleor heterocycle. W⁵ may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms.The W⁵ rings are saturated when containing 3 ring atoms, saturated ormono-unsaturated when containing 4 ring atoms, saturated, or mono- ordi-unsaturated when containing 5 ring atoms, and saturated, mono- ordi-unsaturated, or aromatic when containing 6 ring atoms.

A W⁵ heterocycle may be a monocycle having 3 to 7 ring members (2 to 6carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or abicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3heteroatoms selected from N, O, P, and S). W⁵ heterocyclic monocyclesmay have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatomsselected from N, O, and S); or 5 or 6 ring atoms (3 to 5 carbon atomsand 1 to 2 heteroatoms selected from N and S). W⁵ heterocyclic bicycleshave 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatomsselected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or[6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6]system. The W⁵ heterocycle may be bonded to Y² through a carbon,nitrogen, sulfur or other atom by a stable covalent bond.

W⁵ heterocycles include for example, pyridyl, dihydropyridyl isomers,piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl,imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl,thiofuranyl, thienyl, and pyrrolyl. W⁵ also includes, but is not limitedto, examples such as:

W⁵ carbocycles and heterocycles may be independently substituted with 0to 3 R² groups, as defined above. For example, substituted W⁵carbocycles include:

Examples of substituted phenyl carbocycles include:

Linking Groups and Linkers

The invention provides conjugates that comprise an immuno-modulatorycompound that is linked to one or more phosphonate groups eitherdirectly (e.g. through a covalent bond) or through a linking group (i.e.a linker). The nature of the linker is not critical provided it does notinterfere with the ability of the phosphonate containing compound tofunction as a therapeutic agent. The phosphonate or the linker can belinked to the compound (e.g. a compound of Formulae 500-547) at anysynthetically feasible position on the compound by removing a hydrogenor any portion of the compound to provide an open valence for attachmentof the phosphonate or the linker.

In one embodiment of the invention the linking group or linker (whichcan be designated “L”) can include all or a portions of the group A⁰,A¹, A², or W³ described herein.

In another embodiment of the invention the linking group or linker has amolecular weight of from about 20 daltons to about 400 daltons.

In another embodiment of the invention the linking group or linker has alength of about 5 angstroms to about 300 angstroms.

In another embodiment of the invention the linking group or linkerseparates the DRUG and a P(═Y¹) residue by about 5 angstroms to about200 angstroms, inclusive, in length.

In another embodiment of the invention the linking group or linker is adivalent, branched or unbranched, saturated or unsaturated, hydrocarbonchain, having from 2 to 25 carbon atoms, wherein one or more (e.g. 1, 2,3, or 4) of the carbon atoms is optionally replaced by (—O—), andwherein the chain is optionally substituted on carbon with one or more(e.g. 1, 2, 3, or 4) substituents selected from (C₁-C₆)alkoxy,(C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido, cyano, nitro, halo,hydroxy, oxo (═O), carboxy, aryl, aryloxy, heteroaryl, andheteroaryloxy.

In another embodiment of the invention the linking group or linker is ofthe formula W-A wherein A is (C₁-C₂₄)alkyl, (C₂-C₂₄)alkenyl,(C₂-C₂₄)alkynyl, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl or a combinationthereof, wherein W is —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—,—S—, —S(O)—, —S(O)₂—, —N(R)—, —C(═O)—, or a direct bond; wherein each Ris independently H or (C₁-C₆)alkyl.

In another embodiment of the invention the linking group or linker is adivalent radical formed from a peptide.

In another embodiment of the invention the linking group or linker is adivalent radical formed from an amino acid.

In another embodiment of the invention the linking group or linker is adivalent radical formed from poly-L-glutamic acid, poly-L-aspartic acid,poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine,poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine,poly-L-lysine or poly-L-lysine-L-tyrosine.

In another embodiment of the invention the linking group or linker is ofthe formula W—(CH₂)_(n) wherein, n is between about 1 and about 10; andW is —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—,—S(O)₂—, —C(═O)—, —N(R)—, or a direct bond; wherein each R isindependently H or (C₁-C₆)alkyl.

In another embodiment of the invention the linking group or linker ismethylene, ethylene, or propylene.

In another embodiment of the invention the linking group or linker isattached to the phosphonate group through a carbon atom of the linker.

Compounds

The compounds of the invention include those with immuno-modulatoryactivity. The compounds of the inventions bear one or more (e.g. 1, 2,3, or 4) phosphonate groups, which may be a prodrug moiety.

Typically, compounds of the invention have a molecular weight of fromabout 400 amu to about 10,000 amu; in a specific embodiment of theinvention, compounds have a molecular weight of less than about 5000amu; in another specific embodiment of the invention, compounds have amolecular weight of less than about 2500 amu; in another specificembodiment of the invention, compounds have a molecular weight of lessthan about 1000 amu; in another specific embodiment of the invention,compounds have a molecular weight of less than about 800 amu; in anotherspecific embodiment of the invention, compounds have a molecular weightof less than about 600 amu; and in another specific embodiment of theinvention, compounds have a molecular weight of less than about 600 amuand a molecular weight of greater than about 400 amu.

The compounds of the invention also typically have a logD(polarity) lessthan about 5. In one embodiment the invention provides compounds havinga logD less than about 4; in another one embodiment the inventionprovides compounds having a logD less than about 3; in another oneembodiment the invention provides compounds having a logD greater thanabout −5; in another one embodiment the invention provides compoundshaving a logD greater than about −3; and in another one embodiment theinvention provides compounds having a logD greater than about 0 and lessthan about 3.

Selected substituents within the compounds of the invention are presentto a recursive degree. In this context, “recursive substituent” meansthat a substituent may recite another instance of itself. Because of therecursive nature of such substituents, theoretically, a large number maybe present in any given claim. For example, R^(x) contains a R^(y)substituent. R^(y) can be R², which in turn can be R³. If R³ is selectedto be R^(3c), then a second instance of R^(x) can be selected. One ofordinary skill in the art of medicinal chemistry understands that thetotal number of such substituents is reasonably limited by the desiredproperties of the compound intended. Such properties include, by ofexample and not limitation, physical properties such as molecularweight, solubility or log P, application properties such as activityagainst the intended target, and practical properties such as ease ofsynthesis.

By way of example and not limitation, W³, R^(y) and R³ are all recursivesubstituents in certain claims. Typically, each of these mayindependently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7,6, 5, 4, 3, 2, 1, or 0, times in a given claim. More typically, each ofthese may independently occur 12 or fewer times in a given claim. Moretypically yet, W³ will occur 0 to 8 times, R^(y) will occur 0 to 6 timesand R³ will occur 0 to 10 times in a given claim. Even more typically,W³ will occur 0 to 6 times, R^(y) will occur 0 to 4 times and R³ willoccur 0 to 8 times in a given claim.

Recursive substituents are an intended aspect of the invention. One ofordinary skill in the art of medicinal chemistry understands theversatility of such substituents. To the degree that recursivesubstituents are present in an claim of the invention, the total numberwill be determined as set forth above.

Whenever a compound described herein is substituted with more than oneof the same designated group, e.g., “R¹” or “R^(6a)”, then it will beunderstood that the groups may be the same or different, i.e., eachgroup is independently selected. Wavy lines indicate the site ofcovalent bond attachments to the adjoining groups, moieties, or atoms.

The term immuno-modulatory compound also includes pimecrolimus,everolimus, sirolimus, tacrolimus, prednisolone, VX-148, merimepodib,brequinar, thalidomide, BCX-1777, revimid, diprolene, aclometasonedipropionate, hydrocortisone, dexamethasone, leflunomide,methylprednisolone suleptanate, prednisone, clobetasol, MNA-715 (FK778),SMP-114, teriflunomide, halobetasol, ciclesonide, deflazacort,medroxyprogesterone, budesonide, rimexolone, triamcinolone acetonide,fluticasone, mometasone furoate, methylprednisolone aceponate,cyclosporin A, tacrolimus, mycophenolate, ANA-245, immunosuppressivemacrolide, methotrexate, PNP-405, MDL-74428,9-(3,3-dimethyl-5-phosphonopentyl) guanine, DADMe-IMMG, CP-690,550,mycophenate, cyclosporin, and mizoribine.

In one embodiment of the invention, the compound is in isolated andpurified form. Generally, the term “isolated and purified” means thatthe compound is significantly free of biological materials (e.g. blood,cells, etc.). In one specific embodiment of the invention, the termmeans that the compound or conjugate of the invention is at least about50% pure by weight in a mixture; in another specific embodiment, theterm means that the compound or conjugate of the invention is at leastabout 75% pure by weight in a mixture; in another specific embodiment,the term means that the compound or conjugate of the invention is atleast about 90% pure by weight in a mixture; in another specificembodiment, the term means that the compound or conjugate of theinvention is at least about 98% pure by weight in a mixture; and inanother embodiment, the term means that the compound or conjugate of theinvention is at least about 99% pure by weight in a mixture. In anotherspecific embodiment, the invention provides a compound or conjugate ofthe invention that has been synthetically prepared (e.g. prepared exvivo).

Intracellular Targeting

The phosphonate group of the compounds of the invention may cleave invivo in stages after they have reached the desired site of action, i.e.inside a cell. One mechanism of action inside a cell may entail a firstcleavage, e.g. by esterase, to provide a negatively-charged “locked-in”intermediate. Cleavage of a terminal ester grouping in a compound of theinvention thus affords an unstable intermediate which releases anegatively charged “locked in” intermediate.

After passage inside a cell, intracellular enzymatic cleavage ormodification of the phosphonate or prodrug compound may result in anintracellular accumulation of the cleaved or modified compound by a“trapping” mechanism. The cleaved or modified compound may then be“locked-in” the cell by a significant change in charge, polarity, orother physical property change which decreases the rate at which thecleaved or modified compound can exit the cell, relative to the rate atwhich it entered as the phosphonate prodrug. Other mechanisms by which atherapeutic effect are achieved may be operative as well. Enzymes whichare capable of an enzymatic activation mechanism with the phosphonateprodrug compounds of the invention include, but are not limited to,amidases, esterases, microbial enzymes, phospholipases, cholinesterases,and phosphatases.

From the foregoing, it will be apparent that many different drugs can bederivatized in accord with the present invention. Numerous such drugsare specifically mentioned herein. However, it should be understood thatthe discussion of drug families and their specific members forderivatization according to this invention is not intended to beexhaustive, but merely illustrative.

In one embodiment of the invention, the compound is not an antiviralagent compound. In another embodiment the compound is not a nucleosidecompound. In another embodiment the compound is not an IMPDH inhibitorcompound. In another embodiment the compound is not an antimetabolitecompound. In another embodiment the compound is not a PNP inhibitor. Inanother embodiment the compound is not a substituted compound of any oneof formulae 500-533, 535-541, or 543-547. In another embodiment thecompound is not a substituted compound of any one of one of formulae1-104, 107-124, or 128-151.

Stereoisomers

The compounds of the invention may have chiral centers, e.g., chiralcarbon or phosphorus atoms. The compounds of the invention thus includeracemic mixtures of all stereoisomers, including enantiomers,diastereomers, and atropisomers. In addition, the compounds of theinvention include enriched or resolved optical isomers at any or allasymmetric, chiral atoms. In other words, the chiral centers apparentfrom the depictions are provided as the chiral isomers or racemicmixtures. Both racemic and diastereomeric mixtures, as well as theindividual optical isomers isolated or synthesized, substantially freeof their enantiomeric or diastereomeric partners, are all within thescope of the invention. The racemic mixtures are separated into theirindividual, substantially optically pure isomers through well-knowntechniques such as, for example, the separation of diastereomeric saltsformed with optically active adjuncts, e.g., acids or bases followed byconversion back to the optically active substances. In most instances,the desired optical isomer is synthesized by means of stereospecificreactions, beginning with the appropriate stereoisomer of the desiredstarting material.

The compounds of the invention can also exist as tautomeric isomers incertain cases. All though only one delocalized resonance structure maybe depicted, all such forms are contemplated within the scope of theinvention. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the invention.

Salts and Hydrates

The compositions of this invention optionally comprise salts of thecompounds herein, especially pharmaceutically acceptable non-toxic saltscontaining, for example, Na⁺, Li⁺, K⁺, Ca⁺² and Mg⁺². Such salts mayinclude those derived by combination of appropriate cations such asalkali and alkaline earth metal ions or ammonium and quaternary aminoions with an acid anion moiety, typically a carboxylic acid. Monovalentsalts are preferred if a water soluble salt is desired.

Metal salts typically are prepared by reacting the metal hydroxide witha compound of this invention. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonicacids, to basic centers, typically amines, or to acidic groups. Finally,it is to be understood that the compositions herein comprise compoundsof the invention in their un-ionized, as well as zwitterionic form, andcombinations with stoichiometric amounts of water as in hydrates.

Also included within the scope of this invention are the salts of theparental compounds with one or more amino acids. Any of the amino acidsdescribed above are suitable, especially the naturally-occurring aminoacids found as protein components, although the amino acid typically isone bearing a side chain with a basic or acidic group, e.g., lysine,arginine or glutamic acid, or a neutral group such as glycine, serine,threonine, alanine, isoleucine, or leucine.

Methods of Inhibition of Immuno-Modulation

Another aspect of the invention relates to methods of inhibiting theactivity of immuno-modulators comprising the step of treating a samplesuspected of containing an immuno-modulator with a composition of theinvention.

Compositions of the invention may act as inhibitors ofimmune-modulation, as intermediates for such inhibitors or have otherutilities as described below. The inhibitors will bind to locations onthe surface or in a cavity of an immuno-modulator having a geometryunique to immuno-modulators. Compositions binding immuno-modulators maybind with varying degrees of reversibility. Those compounds bindingsubstantially irreversibly are ideal candidates for use in this methodof the invention. Once labeled, the substantially irreversibly bindingcompositions are useful as probes for the detection ofimmune-modulation. Accordingly, the invention relates to methods ofdetecting immune-modulation in a sample suspected of containing animmuno-modulator comprising the steps of: treating a sample suspected ofcontaining an immuno-modulator with a composition comprising a compoundof the invention bound to a label; and observing the effect of thesample on the activity of the label. Suitable labels are well known inthe diagnostics field and include stable free radicals, fluorophores,radioisotopes, enzymes, chemiluminescent groups and chromogens. Thecompounds herein are labeled in conventional fashion using functionalgroups such as hydroxyl or amino.

Within the context of the invention samples suspected of containing animmuno-modulator include natural or man-made materials such as livingorganisms; tissue or cell cultures; biological samples such asbiological material samples (blood, serum, urine, cerebrospinal fluid,tears, sputum, saliva, tissue samples, and the like); laboratorysamples; food, water, or air samples; bioproduct samples such asextracts of cells, particularly recombinant cells synthesizing a desiredglycoprotein; and the like. Typically the sample will be suspected ofcontaining an immuno-modulator. Samples can be contained in any mediumincluding water and organic solvent/water mixtures. Samples includeliving organisms such as humans, and man made materials such as cellcultures.

The treating step of the invention comprises adding the composition ofthe invention to the sample or it comprises adding a precursor of thecomposition to the sample. The addition step comprises any method ofadministration as described above.

If desired, the activity of an immuno-modulator, after application ofthe composition, can be observed by any method including direct andindirect methods of detecting imm, uno-modulator activity. Quantitative,qualitative, and semiquantitative methods of determiningimmuno-modulation activity are all contemplated. Typically one of thescreening methods described above are applied, however, any other methodsuch as observation of the physiological properties of a living organismare also applicable.

However, in screening compounds capable of inhibiting immuno-modulationit should be kept in mind that the results of enzyme assays may notcorrelate with cell culture assays. Thus, a cell based assay should bethe primary screening tool.

Screens for Immuno-Modulating Inhibitors

Compositions of the invention are screened for inhibitory activityagainst immuno-modulators by any of the conventional techniques forevaluating enzyme activity. Within the context of the invention,typically compositions are first screened for inhibition ofimmuno-modulators in vitro and compositions showing inhibitory activityare then screened for activity in vivo. Compositions having in vitro Ki(inhibitory constants) of less then about 5×10⁻⁶ M, typically less thanabout 1×10⁻⁷ M and preferably less than about 5×10⁻⁸ M are preferred forin vivo use.

Useful in vitro screens have been described in detail and will not beelaborated here. However, the examples describe suitable in vitroassays.

Pharmaceutical Formulations

The compounds of this invention are formulated with conventionalcarriers and excipients, which will be selected in accord with ordinarypractice. Tablets will contain excipients, glidants, fillers, bindersand the like. Aqueous formulations are prepared in sterile form, andwhen intended for delivery by other than oral administration generallywill be isotonic. All formulations will optionally contain excipientssuch as those set forth in the Handbook of Pharmaceutical Excipients(1986). Excipients include ascorbic acid and other antioxidants,chelating agents such as EDTA, carbohydrates such as dextrin,hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and thelike. The pH of the formulations ranges from about 3 to about 11, but isordinarily about 7 to 10.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations. Theformulations, both for veterinary and for human use, of the inventioncomprise at least one active ingredient, as above defined, together withone or more acceptable carriers therefor and optionally othertherapeutic ingredients. The carrier(s) must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand physiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withthe carrier which constitutes one or more accessory ingredients. Ingeneral the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both, and then, if necessary, shapingthe product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas a powder or granules, optionally mixed with a binder, lubricant,inert diluent, preservative, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and optionally are formulatedso as to provide slow or controlled release of the active ingredienttherefrom.

For administration to the eye or other external tissues e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w (including active ingredient(s) in a range between 0.1%and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.),preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethyl sulphoxide andrelated analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. The cream should preferablybe a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the present invention compriseone or more compounds of the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, lactosemonohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for administration to the eye include eye dropswherein the active ingredient is dissolved or suspended in a suitablecarrier, especially an aqueous solvent for the active ingredient. Theactive ingredient is preferably present in such formulations in aconcentration of 0.5 to 20%, advantageously 0.5 to 10% particularlyabout 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis of infections as described below.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefor.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compounds of the invention can also be formulated to provide controlledrelease of the active ingredient to allow less frequent dosing or toimprove the pharmacokinetic or toxicity profile of the activeingredient. Accordingly, the invention also provided compositionscomprising one or more compounds of the invention formulated forsustained or controlled release.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses) or against an active infection, themethod of delivery, and the pharmaceutical formulation, and will bedetermined by the clinician using conventional dose escalation studies.It can be expected to be from about 0.0001 to about 100 mg/kg bodyweight per day. Typically, from about 0.01 to about 10 mg/kg body weightper day. More typically, from about 0.01 to about 5 mg/kg body weightper day. More typically, from about 0.05 to about 0.5 mg/kg body weightper day. For example, the daily candidate dose for an adult human ofapproximately 70 kg body weight will range from 1 mg to 1000 mg,preferably between 5 mg and 500 mg, and may take the form of single ormultiple doses.

Routes of Administration

One or more compounds of the invention (herein referred to as the activeingredients) are administered by any route appropriate to the conditionto be treated. Suitable routes include oral, rectal, nasal, topical(including buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural), and the like. It will be appreciated that the preferred routemay vary with for example the condition of the recipient. An advantageof the compounds of this invention is that they are orally bioavailableand can be dosed orally.

Combination Therapy

Active ingredients of the invention are also used in combination withother active ingredients. Such combinations are selected based on thecondition to be treated, cross-reactivities of ingredients andpharmaco-properties of the combination.

It is also possible to combine any compound of the invention with one ormore other active ingredients in a unitary dosage form for simultaneousor sequential administration to a patient. The combination therapy maybe administered as a simultaneous or sequential regimen. Whenadministered sequentially, the combination may be administered in two ormore administrations.

The combination therapy may provide “synergy” and “synergistic effect”,i.e. the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined formulation; (2) delivered by alternationor in parallel as separate formulations; or (3) by some other regimen.When delivered in alternation therapy, a synergistic effect may beattained when the compounds are administered or delivered sequentially,e.g., in separate tablets, pills or capsules, or by different injectionsin separate syringes. In general, during alternation therapy, aneffective dosage of each active ingredient is administered sequentially,i.e. serially, whereas in combination therapy, effective dosages of twoor more active ingredients are administered together.

Metabolites of the Compounds of the Invention

Also falling within the scope of this invention are the in vivometabolic products of the compounds described herein. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled (e.g., C¹⁴ or H³) compound of the invention, administeringit parenterally in a detectable dose (e.g., greater than about 0.5mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man,allowing sufficient time for metabolism to occur (typically about 30seconds to 30 hours) and isolating its conversion products from theurine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS or NMR analysis. In general, analysis of metabolites is done in thesame way as conventional drug metabolism studies well-known to thoseskilled in the art. The conversion products, so long as they are nototherwise found in vivo, are useful in diagnostic assays for therapeuticdosing of the compounds of the invention even if they possess noimmuno-modulation inhibitory activity of their own.

Recipes and methods for determining stability of compounds in surrogategastrointestinal secretions are known. Compounds are defined herein asstable in the gastrointestinal tract where less than about 50 molepercent of the protected groups are deprotected in surrogate intestinalor gastric juice upon incubation for 1 hour at 37° C. Simply because thecompounds are stable to the gastrointestinal tract does not mean thatthey cannot be hydrolyzed in vivo. The phosphonate prodrugs of theinvention typically will be stable in the digestive system but aresubstantially hydrolyzed to the parental drug in the digestive lumen,liver or other metabolic organ, or within cells in general.

Exemplary Methods of Making the Compounds of the Invention.

The invention also relates to methods of making the compositions of theinvention. The compositions are prepared by any of the applicabletechniques of organic synthesis. Many such techniques are well known inthe art. However, many of the known techniques are elaborated inCompendium of Organic Synthetic Methods (John Wiley & Sons, New York),Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T.Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and LeroyWade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade,Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., AdvancedOrganic Chemistry, Third Edition, (John Wiley & Sons, New York, 1985),Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency inModern Organic Chemistry. In 9 Volumes, Barry M. Trost, Editor-in-Chief(Pergamon Press, New York, 1993 printing).

A number of exemplary methods for the preparation of the compositions ofthe invention are provided below. These methods are intended toillustrate the nature of such preparations are not intended to limit thescope of applicable methods.

Generally, the reaction conditions such as temperature, reaction time,solvents, work-up procedures, and the like, will be those common in theart for the particular reaction to be performed. The cited referencematerial, together with material cited therein, contains detaileddescriptions of such conditions. Typically the temperatures will be−100° C. to 200° C., solvents will be aprotic or protic, and reactiontimes will be 10 seconds to 10 days. Work-up typically consists ofquenching any unreacted reagents followed by partition between awater/organic layer system (extraction) and separating the layercontaining the product.

Oxidation and reduction reactions are typically carried out attemperatures near room temperature (about 20° C.), although for metalhydride reductions frequently the temperature is reduced to 0° C. to−100° C., solvents are typically aprotic for reductions and may beeither protic or aprotic for oxidations. Reaction times are adjusted toachieve desired conversions.

Condensation reactions are typically carried out at temperatures nearroom temperature, although for non-equilibrating, kinetically controlledcondensations reduced temperatures (0° C. to −100° C.) are also common.Solvents can be either protic (common in equilibrating reactions) oraprotic (common in kinetically controlled reactions).

Standard synthetic techniques such as azeotropic removal of reactionby-products and use of anhydrous reaction conditions (e.g., inert gasenvironments) are common in the art and will be applied when applicable.

SCHEMES AND EXAMPLES

General aspects of these exemplary methods are described below and inthe Examples. Each of the products of the following processes isoptionally separated, isolated, and/or purified prior to its use insubsequent processes.

Generally, the reaction conditions such as temperature, reaction time,solvents, work-up procedures, and the like, will be those common in theart for the particular reaction to be performed. The cited referencematerial, together with material cited therein, contains detaileddescriptions of such conditions. Typically the temperatures will be−100° C. to 200° C., solvents will be aprotic or protic, and reactiontimes will be 10 seconds to 10 days. Work-up typically consists ofquenching any unreacted reagents followed by partition between awater/organic layer system (extraction) and separating the layercontaining the product.

Oxidation and reduction reactions are typically carried out attemperatures near room temperature (about 20° C.), although for metalhydride reductions frequently the temperature is reduced to 0° C. to−100° C., solvents are typically aprotic for reductions and may beeither protic or aprotic for oxidations. Reaction times are adjusted toachieve desired conversions.

Condensation reactions are typically carried out at temperatures nearroom temperature, although for non-equilibrating, kinetically controlledcondensations reduced temperatures (0° C. to −100° C.) are also common.Solvents can be either protic (common in equilibrating reactions) oraprotic (common in kinetically controlled reactions).

Standard synthetic techniques such as azeotropic removal of reactionby-products and use of anhydrous reaction conditions (e.g., inert gasenvironments) are common in the art and will be applied when applicable.

The terms “treated”, “treating”, “treatment”, and the like, when used inconnection with a chemical synthetic operation, mean contacting, mixing,reacting, allowing to react, bringing into contact, and other termscommon in the art for indicating that one or more chemical entities istreated in such a manner as to convert it to one or more other chemicalentities. This means that “treating compound one with compound two” issynonymous with “allowing compound one to react with compound two”,“contacting compound one with compound two”, “reacting compound one withcompound two”, and other expressions common in the art of organicsynthesis for reasonably indicating that compound one was “treated”,“reacted”, “allowed to react”, etc., with compound two. For example,treating indicates the reasonable and usual manner in which organicchemicals are allowed to react. Normal concentrations (0.01M to 10M,typically 0.1M to 1M), temperatures (−100° C. to 250° C., typically −78°C. to 150° C., more typically −78° C. to 100° C., still more typically0° C. to 100° C.), reaction vessels (typically glass, plastic, metal),solvents, pressures, atmospheres (typically air for oxygen and waterinsensitive reactions or nitrogen or argon for oxygen or watersensitive), etc., are intended unless otherwise indicated. The knowledgeof similar reactions known in the art of organic synthesis are used inselecting the conditions and apparatus for “treating” in a givenprocess. In particular, one of ordinary skill in the art of organicsynthesis selects conditions and apparatus reasonably expected tosuccessfully carry out the chemical reactions of the described processesbased on the knowledge in the art.

Modifications of each of the exemplary schemes and in the examples(hereafter “exemplary schemes”) leads to various analogs of the specificexemplary materials produce. The above-cited citations describingsuitable methods of organic synthesis are applicable to suchmodifications.

In each of the exemplary schemes it may be advantageous to separatereaction products from one another and/or from starting materials. Thedesired products of each step or series of steps is separated and/orpurified (hereinafter separated) to the desired degree of homogeneity bythe techniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; size exclusion; ion exchange; high, medium, and lowpressure liquid chromatography methods and apparatus; small scaleanalytical; simulated moving bed (SMB) and preparative thin or thicklayer chromatography, as well as techniques of small scale thin layerand flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. For example, boiling point, and molecular weightin distillation and sublimation, presence or absence of polar functionalgroups in chromatography, stability of materials in acidic and basicmedia in multiphase extraction, and the like. One skilled in the artwill apply techniques most likely to achieve the desired separation.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L.Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3)283-302). Racemic mixtures of chiral compounds of the invention can beseparated and isolated by any suitable method, including: (1) formationof ionic, diastereomeric salts with chiral compounds and separation byfractional crystallization or other methods, (2) formation ofdiastereomeric compounds with chiral derivatizing reagents, separationof the diastereomers, and conversion to the pure stereoisomers, and (3)separation of the substantially pure or enriched stereoisomers directlyunder chiral conditions.

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds,John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formedby reacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the free,enantiomerically enriched xanthene. A method of determining opticalpurity involves making chiral esters, such as a menthyl ester, e.g., (−)menthyl chloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org.Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrumfor the presence of the two atropisomeric diastereomers. Stablediastereomers of atropisomeric compounds can be separated and isolatedby normal- and reverse-phase chromatography following methods forseparation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO96/15111). By method (3), a racemic mixture of two enantiomers can beseparated by chromatography using a chiral stationary phase (ChiralLiquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, NewYork; Okamoto, (1990) J. of Chromatogr. 513:375-378). Enriched orpurified enantiomers can be distinguished by methods used to distinguishother chiral molecules with asymmetric carbon atoms, such as opticalrotation and circular dichroism.

Examples General Section

A number of exemplary methods for the preparation of compounds of theinvention are provided herein, for example, in the Examples hereinbelow.These methods are intended to illustrate the nature of such preparationsare not intended to limit the scope of applicable methods. Certaincompounds of the invention can be used as intermediates for thepreparation of other compounds of the invention. For example, theinterconversion of various phosphonate compounds of the invention isillustrated below.

Interconversions of the Phosphonates R-LINK-P(O)(OR¹)₂,R-LINK-P(O)(OR¹)(OH) AND R-LINK-P(O)(OH)₂.

The following schemes 32-38 described the preparation of phosphonateesters of the general structure R-link-P(O)(OR¹)₂, in which the groupsR¹ may be the same or different. The R¹ groups attached to a phosphonateester, or to precursors thereto, may be changed using establishedchemical transformations. The interconversion reactions of phosphonatesare illustrated in Scheme S32. The group R in Scheme 32 represents thesubstructure, i.e. the drug “scaffold, to which the substituentlink-P(O)(OR¹)₂ is attached, either in the compounds of the invention,or in precursors thereto. At the point in the synthetic route ofconducting a phosphonate interconversion, certain functional groups in Rmay be protected. The methods employed for a given phosphonatetransformation depend on the nature of the substituent R¹, and of thesubstrate to which the phosphonate group is attached. The preparationand hydrolysis of phosphonate esters is described in Organic PhosphorusCompounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 9ff.

In general, synthesis of phosphonate esters is achieved by coupling anucleophile amine or alcohol with the corresponding activatedphosphonate electrophilic precursor. For example, chlorophosphonateaddition on to 5′-hydroxy of nucleoside is a well known method forpreparation of nucleoside phosphate monoesters. The activated precursorcan be prepared by several well known methods. Chlorophosphonates usefulfor synthesis of the prodrugs are prepared from thesubstituted-1,3-propanediol (Wissner, et al, (1992) J. Med. Chem.35:1650). Chlorophosphonates are made by oxidation of the correspondingchlorophospholanes (Anderson, et al, (1984) J. Org. Chem. 49:1304) whichare obtained by reaction of the substituted diol with phosphorustrichloride. Alternatively, the chlorophosphonate agent is made bytreating substituted-1,3-diols with phosphorusoxychloride (Patois, etal, (1990) J. Chem. Soc. Perkin Trans. I, 1577). Chlorophosphonatespecies may also be generated in situ from corresponding cyclicphosphites (Silverburg, et al., (1996) Tetrahedron lett., 37:771-774),which in turn can be either made from chlorophospholane orphosphoramidate intermediate. Phosphoroflouridate intermediate preparedeither from pyrophosphate or phosphoric acid may also act as precursorin preparation of cyclic prodrugs (Watanabe et al., (1988) Tetrahedronlett., 29:5763-66).

Phosphonate prodrugs of the present invention may also be prepared fromthe free acid by Mitsunobu reactions (Mitsunobu, (1981) Synthesis, 1;Campbell, (1992) J. Org. Chem. 57:6331), and other acid couplingreagents including, but not limited to, carbodiimides (Alexander, et al,(1994) Collect. Czech. Chem. Commun. 59:1853; Casara et al, (1992)Bioorg. Med. Chem. Lett. 2:145; Ohashi et al, (1988) Tetrahedron Lett.,29:1189), and benzotriazolyloxytris-(dimethylamino)phosphonium salts(Campagne et al (1993) Tetrahedron Lett. 34:6743).

Aryl halides undergo Ni⁺² catalyzed reaction with phosphite derivativesto give aryl phosphonate containing compounds (Balthazar, et al (1980)J. Org. Chem. 45:5425). Phosphonates may also be prepared from thechlorophosphonate in the presence of a palladium catalyst using aromatictriflates (Petrakis et al (1987) J. Am. Chem. Soc. 109:2831; Lu et al(1987) Synthesis 726). In another method, aryl phosphonate esters areprepared from aryl phosphates under anionic rearrangement conditions(Melvin (1981) Tetrahedron Lett. 22:3375; Casteel et al (1991)Synthesis, 691). N-Alkoxy aryl salts with alkali met al derivatives ofcyclic alkyl phosphonate provide general synthesis forheteroaryl-2-phosphonate linkers (Redmore (1970) J. Org. Chem. 35:4114).These above mentioned methods can also be extended to compounds wherethe W⁵ group is a heterocycle. Cyclic-1,3-propanyl prodrugs ofphosphonates are also synthesized from phosphonic diacids andsubstituted propane-1,3-diols using a coupling reagent such as1,3-dicyclohexylcarbodiimide (DCC) in presence of a base (e.g.,pyridine). Other carbodiimide based coupling agents like1,3-disopropylcarbodiimide or water soluble reagent,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) canalso be utilized for the synthesis of cyclic phosphonate prodrugs.

The conversion of a phosphonate diester S32.1 into the correspondingphosphonate monoester S32.2 (Scheme 32, Reaction 1) is accomplished by anumber of methods. For example, the ester S32.1 in which R¹ is anaralkyl group such as benzyl, is converted into the monoester compoundS32.2 by reaction with a tertiary organic base such asdiazabicyclooctane (DABCO) or quinuclidine, as described in J. Org.Chem. (1995) 60:2946. The reaction is performed in an inert hydrocarbonsolvent such as toluene or xylene, at about 110° C. The conversion ofthe diester S32.1 in which R¹ is an aryl group such as phenyl, or analkenyl group such as allyl, into the monoester S32.2 is effected bytreatment of the ester S32.1 with a base such as aqueous sodiumhydroxide in acetonitrile or lithium hydroxide in aqueoustetrahydrofuran. Phosphonate diesters S32.1 in which one of the groupsR¹ is aralkyl, such as benzyl, and the other is alkyl, is converted intothe monoesters S32.2 in which R¹ is alkyl by hydrogenation, for exampleusing a palladium on carbon catalyst. Phosphonate diesters in which bothof the groups R¹ are alkenyl, such as allyl, is converted into themonoester S32.2 in which R¹ is alkenyl, by treatment withchlorotris(triphenylphosphine)rhodium (Wilkinson's catalyst) in aqueousethanol at reflux, optionally in the presence of diazabicyclooctane, forexample by using the procedure described in J. Org. Chem. (1973)38:3224, for the cleavage of allyl carboxylates.

The conversion of a phosphonate diester S32.1 or a phosphonate monoesterS32.2 into the corresponding phosphonic acid S32.3 (Scheme 32, Reactions2 and 3) can be effected by reaction of the diester or the monoesterwith trimethylsilyl bromide, as described in J. Chem. Soc., Chem. Comm.,(1979) 739. The reaction is conducted in an inert solvent such as, forexample, dichloromethane, optionally in the presence of a silylatingagent such as bis(trimethylsilyl)trifluoroacetamide, at ambienttemperature. A phosphonate monoester S32.2 in which R¹ is aralkyl suchas benzyl, is converted into the corresponding phosphonic acid S32.3 byhydrogenation over a palladium catalyst, or by treatment with hydrogenchloride in an ethereal solvent such as dioxane. A phosphonate monoesterS32.2 in which R¹ is alkenyl such as, for example, allyl, is convertedinto the phosphonic acid S32.3 by reaction with Wilkinson's catalyst inan aqueous organic solvent, for example in 15% aqueous acetonitrile, orin aqueous ethanol, for example using the procedure described in Helv.Chim. Acta. (1985) 68:618. Palladium catalyzed hydrogenolysis ofphosphonate esters S32.1 in which R¹ is benzyl is described in J. Org.Chem. (1959) 24:434. Platinum-catalyzed hydrogenolysis of phosphonateesters S32.1 in which R¹ is phenyl is described in J. Am. Chem. Soc.(1956) 78:2336.

The conversion of a phosphonate monoester S32.2 into a phosphonatediester S32.1 (Scheme 32, Reaction 4) in which the newly introduced R¹group is alkyl, aralkyl, haloalkyl such as chloroethyl, or aralkyl iseffected by a number of reactions in which the substrate S32.2 isreacted with a hydroxy compound R¹OH, in the presence of a couplingagent. Typically, the second phosphonate ester group is different thanthe first introduced phosphonate ester group, i.e. R¹ is followed by theintroduction of R² where each of R¹ and R² is alkyl, aralkyl, haloalkylsuch as chloroethyl, or aralkyl (Scheme 32, Reaction 4a) whereby S32.2is converted to S32.1a. Suitable coupling agents are those employed forthe preparation of carboxylate esters, and include a carbodiimide suchas dicyclohexylcarbodiimide, in which case the reaction is preferablyconducted in a basic organic solvent such as pyridine, or(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PYBOP, Sigma), in which case the reaction is performed in a polarsolvent such as dimethylformamide, in the presence of a tertiary organicbase such as diisopropylethylamine, or Aldrithiol-2 (Aldrich) in whichcase the reaction is conducted in a basic solvent such as pyridine, inthe presence of a triaryl phosphine such as triphenylphosphine.Alternatively, the conversion of the phosphonate monoester S32.2 to thediester S32.1 is effected by the use of the Mitsunobu reaction, asdescribed above. The substrate is reacted with the hydroxy compoundR¹OH, in the presence of diethyl azodicarboxylate and a triarylphosphinesuch as triphenyl phosphine. Alternatively, the phosphonate monoesterS32.2 is transformed into the phosphonate diester S32.1, in which theintroduced R¹ group is alkenyl or aralkyl, by reaction of the monoesterwith the halide R¹Br, in which R¹ is as alkenyl or aralkyl. Thealkylation reaction is conducted in a polar organic solvent such asdimethylformamide or acetonitrile, in the presence of a base such ascesium carbonate. Alternatively, the phosphonate monoester istransformed into the phosphonate diester in a two step procedure. In thefirst step, the phosphonate monoester S32.2 is transformed into thechloro analog RP(O)(OR¹)Cl by reaction with thionyl chloride or oxalylchloride and the like, as described in Organic Phosphorus Compounds, G.M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 17, and the thus-obtainedproduct RP(O)(OR¹)Cl is then reacted with the hydroxy compound R¹OH, inthe presence of a base such as triethylamine, to afford the phosphonatediester S32.1.

A phosphonic acid R-link-P(O)(OH)₂ is transformed into a phosphonatemonoester RP(O)(OR¹)(OH) (Scheme 32, Reaction 5) by means of the methodsdescribed above of for the preparation of the phosphonate diesterR-link-P(O)(OR¹)₂ S32.1, except that only one molar proportion of thecomponent R¹OH or R¹Br is employed. Dialkyl phosphonates may be preparedaccording to the methods of: Quast et al (1974) Synthesis 490; Stowellet al (1990) Tetrahedron Lett. 3261; U.S. Pat. No. 5,663,159.

A phosphonic acid R-link-P(O)(OH)₂ S32.3 is transformed into aphosphonate diester R-link-P(O)(OR¹)₂ S32.1 (Scheme 32, Reaction 6) by acoupling reaction with the hydroxy compound R¹OH, in the presence of acoupling agent such as Aldrithiol-2 (Aldrich) and triphenylphosphine.The reaction is conducted in a basic solvent such as pyridine.Alternatively, phosphonic acids S32.3 are transformed into phosphonicesters S32.1 in which R¹ is aryl, by means of a coupling reactionemploying, for example, dicyclohexylcarbodiimide in pyridine at ca 70°C. Alternatively, phosphonic acids S32.3 are transformed into phosphonicesters S32.1 in which R¹ is alkenyl, by means of an alkylation reaction.The phosphonic acid is reacted with the alkenyl bromide R¹Br in a polarorganic solvent such as acetonitrile solution at reflux temperature, thepresence of a base such as cesium carbonate, to afford the phosphonicester S32.1.

Preparation of Phosphonate Carbamates.

Phosphonate esters may contain a carbamate linkage. The preparation ofcarbamates is described in Comprehensive Organic Functional GroupTransformations, A. R. Katritzky, ed., Pergamon, 1995, Vol. 6, p. 416ff,and in Organic Functional Group Preparations, by S. R. Sandler and W.Karo, Academic Press, 1986, p. 260ff. The carbamoyl group may be formedby reaction of a hydroxy group according to the methods known in theart, including the teachings of Ellis, US 2002/0103378 A1 and Hajima,U.S. Pat. No. 6,018,049.

Scheme 33 illustrates various methods by which the carbamate linkage issynthesized. As shown in Scheme 33, in the general reaction generatingcarbamates, an alcohol S33.1, is converted into the activated derivativeS33.2 in which Lv is a leaving group such as halo, imidazolyl,benztriazolyl and the like, as described herein. The activatedderivative S33.2 is then reacted with an amine S33.3, to afford thecarbamate product S33.4. Examples 1-7 in Scheme 33 depict methods bywhich the general reaction is effected. Examples 8-10 illustratealternative methods for the preparation of carbamates.

Scheme 33, Example 1 illustrates the preparation of carbamates employinga chloroformyl derivative of the alcohol S33.5. In this procedure, thealcohol S33.5 is reacted with phosgene, in an inert solvent such astoluene, at about 0° C., as described in Org. Syn. Coll. Vol. 3, 167,1965, or with an equivalent reagent such as trichloromethoxychloroformate, as described in Org. Syn. Coll. Vol. 6, 715, 1988, toafford the chloroformate S33.6. The latter compound is then reacted withthe amine component S33.3, in the presence of an organic or inorganicbase, to afford the carbamate S33.7. For example, the chloroformylcompound S33.6 is reacted with the amine S33.3 in a water-misciblesolvent such as tetrahydrofuran, in the presence of aqueous sodiumhydroxide, as described in Org. Syn. Coll. Vol. 3, 167, 1965, to yieldthe carbamate S33.7. Alternatively, the reaction is performed indichloromethane in the presence of an organic base such asdiisopropylethylamine or dimethylaminopyridine.

Scheme 33, Example 2 depicts the reaction of the chloroformate compoundS33.6 with imidazole to produce the imidazolide S33.8. The imidazolideproduct is then reacted with the amine S33.3 to yield the carbamateS33.7. The preparation of the imidazolide is performed in an aproticsolvent such as dichloromethane at 0°, and the preparation of thecarbamate is conducted in a similar solvent at ambient temperature,optionally in the presence of a base such as dimethylaminopyridine, asdescribed in J. Med. Chem., 1989, 32, 357.

Scheme 33 Example 3, depicts the reaction of the chloroformate S33.6with an activated hydroxyl compound R″OH, to yield the mixed carbonateester S33.10. The reaction is conducted in an inert organic solvent suchas ether or dichloromethane, in the presence of a base such asdicyclohexylamine or triethylamine. The hydroxyl component R″OH isselected from the group of compounds S33.19-S33.24 shown in Scheme 33,and similar compounds. For example, if the component R″OH ishydroxybenztriazole S33.19, N-hydroxysuccinimide S33.20, orpentachlorophenol, S33.21, the mixed carbonate S33.10 is obtained by thereaction of the chloroformate with the hydroxyl compound in an etherealsolvent in the presence of dicyclohexylamine, as described in Can. J.Chem., 1982, 60, 976. A similar reaction in which the component R″OH ispentafluorophenol S33.22 or 2-hydroxypyridine S33.23 is performed in anethereal solvent in the presence of triethylamine, as described in Syn.,1986, 303, and Chem. Ber. 118, 468, 1985.

Scheme 33 Example 4 illustrates the preparation of carbamates in whichan alkyloxycarbonylimidazole S33.8 is employed. In this procedure, analcohol S33.5 is reacted with an equimolar amount of carbonyldiimidazole S33.11 to prepare the intermediate S33.8. The reaction isconducted in an aprotic organic solvent such as dichloromethane ortetrahydrofuran. The acyloxyimidazole S33.8 is then reacted with anequimolar amount of the amine R′NH₂ to afford the carbamate S33.7. Thereaction is performed in an aprotic organic solvent such asdichloromethane, as described in Tet. Lett., 42, 2001, 5227, to affordthe carbamate S33.7.

Scheme 33, Example 5 illustrates the preparation of carbamates by meansof an intermediate alkoxycarbonylbenztriazole S33.13. In this procedure,an alcohol ROH is reacted at ambient temperature with an equimolaramount of benztriazole carbonyl chloride S33.12, to afford thealkoxycarbonyl product S33.13. The reaction is performed in an organicsolvent such as benzene or toluene, in the presence of a tertiaryorganic amine such as triethylamine, as described in Synthesis., 1977,704. The product is then reacted with the amine R′NH₂ to afford thecarbamate S33.7. The reaction is conducted in toluene or ethanol, atfrom ambient temperature to about 80° C. as described in Synthesis.,1977, 704.

Scheme 33, Example 6 illustrates the preparation of carbamates in whicha carbonate (R′O)₂CO, S33.14, is reacted with an alcohol S33.5 to affordthe intermediate alkyloxycarbonyl intermediate S33.15. The latterreagent is then reacted with the amine R′NH₂ to afford the carbamateS33.7. The procedure in which the reagent S33.15 is derived fromhydroxybenztriazole S33.19 is described in Synthesis, 1993, 908; theprocedure in which the reagent S33.15 is derived fromN-hydroxysuccinimide S33.20 is described in Tet. Lett., 1992, 2781; theprocedure in which the reagent S33.15 is derived from 2-hydroxypyridineS33.23 is described in Tet. Lett., 1991, 4251; the procedure in whichthe reagent S33.15 is derived from 4-nitrophenol S33.24 is described inSynthesis. 1993, 103. The reaction between equimolar amounts of thealcohol ROH and the carbonate S33.14 is conducted in an inert organicsolvent at ambient temperature.

Scheme 33, Example 7 illustrates the preparation of carbamates fromalkoxycarbonyl azides S33.16. In this procedure, an alkyl chloroformateS33.6 is reacted with an azide, for example sodium azide, to afford thealkoxycarbonyl azide S33.16. The latter compound is then reacted with anequimolar amount of the amine R′NH₂ to afford the carbamate S33.7. Thereaction is conducted at ambient temperature in a polar aprotic solventsuch as dimethylsulfoxide, for example as described in Synthesis., 1982,404.

Scheme 33, Example 8 illustrates the preparation of carbamates by meansof the reaction between an alcohol ROH and the chloroformyl derivativeof an amine S33.17. In this procedure, which is described in SyntheticOrganic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 647, thereactants are combined at ambient temperature in an aprotic solvent suchas acetonitrile, in the presence of a base such as triethylamine, toafford the carbamate S33.7.

Scheme 33, Example 9 illustrates the preparation of carbamates by meansof the reaction between an alcohol ROH and an isocyanate S33.18. In thisprocedure, which is described in Synthetic Organic Chemistry, R. B.Wagner, H. D. Zook, Wiley, 1953, p. 645, the reactants are combined atambient temperature in an aprotic solvent such as ether ordichloromethane and the like, to afford the carbamate S33.7.

Scheme 33, Example 10 illustrates the preparation of carbamates by meansof the reaction between an alcohol ROH and an amine R′NH₂. In thisprocedure, which is described in Chem. Lett. 1972, 373, the reactantsare combined at ambient temperature in an aprotic organic solvent suchas tetrahydrofuran, in the presence of a tertiary base such astriethylamine, and selenium. Carbon monoxide is passed through thesolution and the reaction proceeds to afford the carbamate S33.7.

Preparation of Carboalkoxy-Substituted Phosphonate Bisamidates,Monoamidates, Diesters and Monoesters.

A number of methods are available for the conversion of phosphonic acidsinto amidates and esters. In one group of methods, the phosphonic acidis either converted into an isolated activated intermediate such as aphosphoryl chloride, or the phosphonic acid is activated in situ forreaction with an amine or a hydroxy compound.

The conversion of phosphonic acids into phosphoryl chlorides isaccomplished by reaction with thionyl chloride, for example as describedin J. Gen. Chem. USSR, 1983, 53, 480, Zh. Obschei Khim., 1958, 28, 1063,or J. Org. Chem., 1994, 59, 6144, or by reaction with oxalyl chloride,as described in J. Am. Chem. Soc., 1994, 116, 3251, or J. Org. Chem.,1994, 59, 6144, or by reaction with phosphorus pentachloride, asdescribed in J. Org. Chem., 2001, 66, 329, or in J. Med. Chem., 1995,38, 1372. The resultant phosphoryl chlorides are then reacted withamines or hydroxy compounds in the presence of a base to afford theamidate or ester products.

Phosphonic acids are converted into activated imidazolyl derivatives byreaction with carbonyl diimidazole, as described in J. Chem. Soc., Chem.Comm. (1991) 312, or Nucleosides & Nucleotides (2000) 19:1885. Activatedsulfonyloxy derivatives are obtained by the reaction of phosphonic acidswith trichloromethylsulfonyl chloride or withtriisopropylbenzenesulfonyl chloride, as described in Tet. Lett. (1996)7857, or Bioorg. Med. Chem. Lett. (1998) 8:663. The activatedsulfonyloxy derivatives are then reacted with amines or hydroxycompounds to afford amidates or esters.

Alternatively, the phosphonic acid and the amine or hydroxy reactant arecombined in the presence of a diimide coupling agent. The preparation ofphosphonic amidates and esters by means of coupling reactions in thepresence of dicyclohexyl carbodiimide is described, for example, in J.Chem. Soc., Chem. Comm. (1991) 312 or Coll. Czech. Chem. Comm. (1987)52:2792. The use of ethyl dimethylaminopropyl carbodiimide foractivation and coupling of phosphonic acids is described in Tet. Lett.,(2001) 42:8841, or Nucleosides & Nucleotides (2000) 19:1885.

A number of additional coupling reagents have been described for thepreparation of amidates and esters from phosphonic acids. The agentsinclude Aldrithiol-2, and PYBOP and BOP, as described in J. Org. Chem.,1995, 60, 5214, and J. Med. Chem. (1997) 40:3842,mesitylene-2-sulfonyl-3-nitro-1,2,4-triazole (MSNT), as described in J.Med. Chem. (1996) 39:4958, diphenylphosphoryl azide, as described in J.Org. Chem. (1984) 49:1158,1-(2,4,6-triisopropylbenzenesulfonyl-3-nitro-1,2,4-triazole (TPSNT) asdescribed in Bioorg. Med. Chem. Lett. (1998) 8:1013,bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP), asdescribed in Tet. Lett., (1996) 37:3997,2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphinane, as described inNucleosides Nucleotides 1995, 14, 871, and diphenyl chlorophosphate, asdescribed in J. Med. Chem., 1988, 31, 1305.

Phosphonic acids are converted into amidates and esters by means of theMitsunobu reaction, in which the phosphonic acid and the amine orhydroxy reactant are combined in the presence of a triaryl phosphine anda dialkyl azodicarboxylate. The procedure is described in Org. Lett.,2001, 3, 643, or J. Med. Chem., 1997, 40, 3842.

Phosphonic esters are also obtained by the reaction between phosphonicacids and halo compounds, in the presence of a suitable base. The methodis described, for example, in Anal. Chem., 1987, 59, 1056, or J. Chem.Soc. Perkin Trans., I, 1993, 19, 2303, or J. Med. Chem., 1995, 38, 1372,or Tet. Lett., 2002, 43, 1161.

Schemes 34-37 illustrate the conversion of phosphonate esters andphosphonic acids into carboalkoxy-substituted phosphonbisamidates(Scheme 34), phosphonamidates (Scheme 35), phosphonate monoesters(Scheme 36) and phosphonate diesters, (Scheme 37). Scheme 38 illustratessynthesis of gem-dialkyl amino phosphonate reagents.

Scheme 34 illustrates various methods for the conversion of phosphonatediesters S34.1 into phosphonbisamidates S34.5. The diester S34.1,prepared as described previously, is hydrolyzed, either to the monoesterS34.2 or to the phosphonic acid S34.6. The methods employed for thesetransformations are described above. The monoester S34.2 is convertedinto the monoamidate S34.3 by reaction with an aminoester S34.9, inwhich the group R² is H or alkyl; the group R^(4b) is a divalentalkylene moiety such as, for example, CHCH₃, CHCH₂CH₃, CH(CH(CH₃)₂),CH(CH₂Ph), and the like, or a side chain group present in natural ormodified aminoacids; and the group R^(5b) is C₁-C₁₂ alkyl, such asmethyl, ethyl, propyl, isopropyl, or isobutyl; C₆-C₂₀ aryl, such asphenyl or substituted phenyl; or C₆-C₂₀ arylalkyl, such as benzyl orbenzyhydryl. The reactants are combined in the presence of a couplingagent such as a carbodiimide, for example dicyclohexyl carbodiimide, asdescribed in J. Am. Chem. Soc., (1957) 79:3575, optionally in thepresence of an activating agent such as hydroxybenztriazole, to yieldthe amidate product S34.3. The amidate-forming reaction is also effectedin the presence of coupling agents such as BOP, as described in J. Org.Chem. (1995) 60:5214, Aldrithiol, PYBOP and similar coupling agents usedfor the preparation of amides and esters. Alternatively, the reactantsS34.2 and S34.9 are transformed into the monoamidate S34.3 by means of aMitsunobu reaction. The preparation of amidates by means of theMitsunobu reaction is described in J. Med. Chem. (1995) 38:2742.Equimolar amounts of the reactants are combined in an inert solvent suchas tetrahydrofuran in the presence of a triaryl phosphine and a dialkylazodicarboxylate. The thus-obtained monoamidate ester S34.3 is thentransformed into amidate phosphonic acid S34.4. The conditions used forthe hydrolysis reaction depend on the nature of the R¹ group, asdescribed previously. The phosphonic acid amidate S34.4 is then reactedwith an aminoester S34.9, as described above, to yield the bisamidateproduct S34.5, in which the amino substituents are the same ordifferent. Alternatively, the phosphonic acid S34.6 may be treated withtwo different amino ester reagents simulataneously, i.e. S34.9 where R²,R^(4b) or R^(5b) are different. The resulting mixture of bisamidateproducts S34.5 may then be separable, e.g. by chromatography.

An example of this procedure is shown in Scheme 34, Example 1. In thisprocedure, a dibenzyl phosphonate S34.14 is reacted withdiazabicyclooctane (DABCO) in toluene at reflux, as described in J. Org.Chem., 1995, 60, 2946, to afford the monobenzyl phosphonate S34.15. Theproduct is then reacted with equimolar amounts of ethyl alaninate S34.16and dicyclohexyl carbodiimide in pyridine, to yield the amidate productS34.17. The benzyl group is then removed, for example by hydrogenolysisover a palladium catalyst, to give the monoacid product S34.18 which maybe unstable according to J. Med. Chem. (1997) 40(23):3842. This compoundS34.18 is then reacted in a Mitsunobu reaction with ethyl leucinateS34.19, triphenyl phosphine and diethylazodicarboxylate, as described inJ. Med. Chem., 1995, 38, 2742, to produce the bisamidate product S34.20.

Using the above procedures, but employing in place of ethyl leucinateS34.19 or ethyl alaninate S34.16, different aminoesters S34.9, thecorresponding products S34.5 are obtained.

Alternatively, the phosphonic acid S34.6 is converted into thebisamidate S34.5 by use of the coupling reactions described above. Thereaction is performed in one step, in which case the nitrogen-relatedsubstituents present in the product S34.5 are the same, or in two steps,in which case the nitrogen-related substituents can be different.

An example of the method is shown in Scheme 34, Example 2. In thisprocedure, a phosphonic acid S34.6 is reacted in pyridine solution withexcess ethyl phenylalaninate S34.21 and dicyclohexylcarbodiimide, forexample as described in J. Chem. Soc., Chem. Comm., 1991, 1063, to givethe bisamidate product S34.22.

Using the above procedures, but employing, in place of ethylphenylalaninate, different aminoesters S34.9, the corresponding productsS34.5 are obtained.

As a further alternative, the phosphonic acid S34.6 is converted intothe mono or bis-activated derivative S34.7, in which Lv is a leavinggroup such as chloro, imidazolyl, triisopropylbenzenesulfonyloxy etc.The conversion of phosphonic acids into chlorides S34.7 (Lv=Cl) iseffected by reaction with thionyl chloride or oxalyl chloride and thelike, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L.Maeir, eds, Wiley, 1976, p. 17. The conversion of phosphonic acids intomonoimidazolides S34.7 (Lv=imidazolyl) is described in J. Med. Chem.,2002, 45, 1284 and in J. Chem. Soc. Chem. Comm., 1991, 312.Alternatively, the phosphonic acid is activated by reaction withtriisopropylbenzenesulfonyl chloride, as described in Nucleosides andNucleotides, 2000, 10, 1885. The activated product is then reacted withthe aminoester S34.9, in the presence of a base, to give the bisamidateS34.5. The reaction is performed in one step, in which case the nitrogensubstituents present in the product S34.5 are the same, or in two steps,via the intermediate S34.11, in which case the nitrogen substituents canbe different.

Examples of these methods are shown in Scheme 34, Examples 3 and 5. Inthe procedure illustrated in Scheme 34, Example 3, a phosphonic acidS34.6 is reacted with ten molar equivalents of thionyl chloride, asdescribed in Zh. Obschei Khim., 1958, 28, 1063, to give the dichlorocompound S34.23. The product is then reacted at reflux temperature in apolar aprotic solvent such as acetonitrile, and in the presence of abase such as triethylamine, with butyl serinate S34.24 to afford thebisamidate product S34.25.

Using the above procedures, but employing, in place of butyl serinateS34.24, different aminoesters S34.9, the corresponding products S34.5are obtained.

In the procedure illustrated in Scheme 34, Example 5, the phosphonicacid S34.6 is reacted, as described in J. Chem. Soc. Chem. Comm., 1991,312, with carbonyl diimidazole to give the imidazolide S34.S32. Theproduct is then reacted in acetonitrile solution at ambient temperature,with one molar equivalent of ethyl alaninate S34.33 to yield themonodisplacement product S34.S34. The latter compound is then reactedwith carbonyl diimidazole to produce the activated intermediate S34.35,and the product is then reacted, under the same conditions, with ethylN-methylalaninate S34.33a to give the bisamidate product S34.36.

Using the above procedures, but employing, in place of ethyl alaninateS34.33 or ethyl N-methylalaninate S34.33a, different aminoesters S34.9,the corresponding products S34.5 are obtained.

The intermediate monoamidate S34.3 is also prepared from the monoesterS34.2 by first converting the monoester into the activated derivativeS34.8 in which Lv is a leaving group such as halo, imidazolyl etc, usingthe procedures described above. The product S34.8 is then reacted withan aminoester S34.9 in the presence of a base such as pyridine, to givean intermediate monoamidate product S34.3. The latter compound is thenconverted, by removal of the R¹ group and coupling of the product withthe aminoester S34.9, as described above, into the bisamidate S34.5.

An example of this procedure, in which the phosphonic acid is activatedby conversion to the chloro derivative S34.26, is shown in Scheme 34,Example 4. In this procedure, the phosphonic monobenzyl ester S34.15 isreacted, in dichloromethane, with thionyl chloride, as described in Tet.Letters., 1994, 35, 4097, to afford the phosphoryl chloride S34.26. Theproduct is then reacted in acetonitrile solution at ambient temperaturewith one molar equivalent of ethyl 3-amino-2-methylpropionate S34.27 toyield the monoamidate product S34.28. The latter compound ishydrogenated in ethylacetate over a 5% palladium on carbon catalyst toproduce the monoacid product S34.29. The product is subjected to aMitsunobu coupling procedure, with equimolar amounts of butyl alaninateS34.30, triphenyl phosphine, diethylazodicarboxylate and triethylaminein tetrahydrofuran, to give the bisamidate product S34.31.

Using the above procedures, but employing, in place of ethyl3-amino-2-methylpropionate S34.27 or butyl alaninate S34.30, differentaminoesters S34.9, the corresponding products S34.5 are obtained.

The activated phosphonic acid derivative S34.7 is also converted intothe bisamidate S34.5 via the diamino compound S34.10. The conversion ofactivated phosphonic acid derivatives such as phosphoryl chlorides intothe corresponding amino analogs S34.10, by reaction with ammonia, isdescribed in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir,eds, Wiley, 1976. The bisamino compound S34.10 is then reacted atelevated temperature with a haloester S34.12 (Hal=halogen, i.e. F, Cl,Br, I), in a polar organic solvent such as dimethylformamide, in thepresence of a base such as 4,4-dimethylaminopyridine (DMAP) or potassiumcarbonate, to yield the bisamidate S34.5. Alternatively, S34.6 may betreated with two different amino ester reagents simulataneously, i.e.S34.12 where R^(4b) or R^(5b) are different. The resulting mixture ofbisamidate products S34.5 may then be separable, e.g. by chromatography.

An example of this procedure is shown in Scheme 34, Example 6. In thismethod, a dichlorophosphonate S34.23 is reacted with ammonia to affordthe diamide S34.37. The reaction is performed in aqueous, aqueousalcoholic or alcoholic solution, at reflux temperature. The resultingdiamino compound is then reacted with two molar equivalents of ethyl2-bromo-3-methylbutyrate S34.38, in a polar organic solvent such asN-methylpyrrolidinone at ca. 150° C., in the presence of a base such aspotassium carbonate, and optionally in the presence of a catalyticamount of potassium iodide, to afford the bisamidate product S34.39.

Using the above procedures, but employing, in place of ethyl2-bromo-3-methylbutyrate S34.38, different haloesters S34.12 thecorresponding products S34.5 are obtained.

The procedures shown in Scheme 34 are also applicable to the preparationof bisamidates in which the aminoester moiety incorporates differentfunctional groups. Scheme 34, Example 7 illustrates the preparation ofbisamidates derived from tyrosine. In this procedure, themonoimidazolide S34.32 is reacted with propyl tyrosinate S34.40, asdescribed in Example 5, to yield the monoamidate S34.41. The product isreacted with carbonyl diimidazole to give the imidazolide S34.42, andthis material is reacted with a further molar equivalent of propyltyrosinate to produce the bisamidate product S34.43.

Using the above procedures, but employing, in place of propyl tyrosinateS34.40, different aminoesters S34.9, the corresponding products S34.5are obtained. The aminoesters employed in the two stages of the aboveprocedure can be the same or different, so that bisamidates with thesame or different amino substituents are prepared.

Scheme 35 illustrates methods for the preparation of phosphonatemonoamidates.

In one procedure, a phosphonate monoester S34.1 is converted, asdescribed in Scheme 34, into the activated derivative S34.8. Thiscompound is then reacted, as described above, with an aminoester S34.9,in the presence of a base, to afford the monoamidate product S35.1.

The procedure is illustrated in Scheme 35, Example 1. In this method, amonophenyl phosphonate S35.7 is reacted with, for example, thionylchloride, as described in J. Gen. Chem. USSR., 1983, 32, 367, to givethe chloro product S35.8. The product is then reacted, as described inScheme 34, with ethyl alaninate, S3, to yield the amidate S35.10.

Using the above procedures, but employing, in place of ethyl alaninateS35.9, different aminoesters S34.9, the corresponding products S35.1 areobtained.

Alternatively, the phosphonate monoester S34.1 is coupled, as describedin Scheme 34, with an aminoester S34.9 to produce the amidate, S335.1.If necessary, the R¹ substituent is then altered, by initial cleavage toafford the phosphonic acid S35.2. The procedures for this transformationdepend on the nature of the R¹ group, and are described above. Thephosphonic acid is then transformed into the ester amidate productS35.3, by reaction with the hydroxy compound R³OH, in which the group R³is aryl, heterocycle, alkyl, cycloalkyl, haloalkyl etc, using the samecoupling procedures (carbodiimide, Aldrithiol-2, PYBOP, Mitsunobureaction etc) described in Scheme 34 for the coupling of amines andphosphonic acids.

Examples of this method are shown in Scheme 35, Examples and 2 and 3. Inthe sequence shown in Example 2, a monobenzyl phosphonate S35.11 istransformed by reaction with ethyl alaninate, using one of the methodsdescribed above, into the monoamidate S35.12. The benzyl group is thenremoved by catalytic hydrogenation in ethylacetate solution over a 5%palladium on carbon catalyst, to afford the phosphonic acid amidateS35.13. The product is then reacted in dichloromethane solution atambient temperature with equimolar amounts of1-(dimethylaminopropyl)-3-ethylcarbodiimide and trifluoroethanol S35.14,for example as described in Tet. Lett., 2001, 42, 8841, to yield theamidate ester S35.15.

In the sequence shown in Scheme 35, Example 3, the monoamidate S35.13 iscoupled, in tetrahydrofuran solution at ambient temperature, withequimolar amounts of dicyclohexyl carbodiimide and4-hydroxy-N-methylpiperidine S35.16, to produce the amidate esterproduct S35.17.

Using the above procedures, but employing, in place of the ethylalaninate product S35.12 different monoacids S35.2, and in place oftrifluoroethanol S35.14 or 4-hydroxy-N-methylpiperidine S35.16,different hydroxy compounds R³OH, the corresponding products S35.3 areobtained.

Alternatively, the activated phosphonate ester S34.8 is reacted withammonia to yield the amidate S35.4. The product is then reacted, asdescribed in Scheme 34, with a haloester S35.5, in the presence of abase, to produce the amidate product S35.6. If appropriate, the natureof the R¹ group is changed, using the procedures described above, togive the product S35.3. The method is illustrated in Scheme 35, Example4. In this sequence, the monophenyl phosphoryl chloride S35.18 isreacted, as described in Scheme 34, with ammonia, to yield the aminoproduct S35.19. This material is then reacted in N-methylpyrrolidinonesolution at 170° with butyl 2-bromo-3-phenylpropionate S35.20 andpotassium carbonate, to afford the amidate product S35.21.

Using these procedures, but employing, in place of butyl2-bromo-3-phenylpropionate S35.20, different haloesters S35.5, thecorresponding products S35.6 are obtained.

The monoamidate products S35.3 are also prepared from the doublyactivated phosphonate derivatives S34.7. In this procedure, examples ofwhich are described in Synlett., 1998, 1, 73, the intermediate S34.7 isreacted with a limited amount of the aminoester S34.9 to give themono-displacement product S34.11. The latter compound is then reactedwith the hydroxy compound R³OH in a polar organic solvent such asdimethylformamide, in the presence of a base such asdiisopropylethylamine, to yield the monoamidate ester S35.3.

The method is illustrated in Scheme 35, Example 5. In this method, thephosphoryl dichloride S35.22 is reacted in dichloromethane solution withone molar equivalent of ethyl N-methyl tyrosinate S35.23 anddimethylaminopyridine, to generate the monoamidate S35.24. The productis then reacted with phenol S35.25 in dimethylformamide containingpotassium carbonate, to yield the ester amidate product S35.26.

Using these procedures, but employing, in place of ethyl N-methyltyrosinate S35.23 or phenol S35.25, the aminoesters 34.9 and/or thehydroxy compounds R³OH, the corresponding products S35.3 are obtained.

Scheme 36 illustrates methods for the preparation ofcarboalkoxy-substituted phosphonate diesters in which one of the estergroups incorporates a carboalkoxy substituent.

In one procedure, a phosphonate monoester S34.1, prepared as describedabove, is coupled, using one of the methods described above, with ahydroxyester S36.1, in which the groups R^(4b) and R^(5b) are asdescribed in Scheme 34. For example, equimolar amounts of the reactantsare coupled in the presence of a carbodiimide such as dicyclohexylcarbodiimide, as described in Aust. J. Chem., 1963, 609, optionally inthe presence of dimethylaminopyridine, as described in Tet., 1999, 55,12997. The reaction is conducted in an inert solvent at ambienttemperature.

The procedure is illustrated in Scheme 36, Example 1. In this method, amonophenyl phosphonate S36.9 is coupled, in dichloromethane solution inthe presence of dicyclohexyl carbodiimide, with ethyl3-hydroxy-2-methylpropionate S36.10 to yield the phosphonate mixeddiester S36.11.

Using this procedure, but employing, in place of ethyl3-hydroxy-2-methylpropionate S36.10, different hydroxyesters S33.1, thecorresponding products S33.2 are obtained.

The conversion of a phosphonate monoester S34.1 into a mixed diesterS36.2 is also accomplished by means of a Mitsunobu coupling reactionwith the hydroxyester S36.1, as described in Org. Lett., 2001, 643. Inthis method, the reactants 34.1 and S36.1 are combined in a polarsolvent such as tetrahydrofuran, in the presence of a triarylphosphineand a dialkyl azodicarboxylate, to give the mixed diester S36.2. The R¹substituent is varied by cleavage, using the methods describedpreviously, to afford the monoacid product S36.3. The product is thencoupled, for example using methods described above, with the hydroxycompound R³OH, to give the diester product S36.4.

The procedure is illustrated in Scheme 36, Example 2. In this method, amonoallyl phosphonate S36.12 is coupled in tetrahydrofuran solution, inthe presence of triphenylphosphine and diethylazodicarboxylate, withethyl lactate S36.13 to give the mixed diester S36.14. The product isreacted with tris(triphenylphosphine) rhodium chloride (Wilkinsoncatalyst) in acetonitrile, as described previously, to remove the allylgroup and produce the monoacid product S36.15. The latter compound isthen coupled, in pyridine solution at ambient temperature, in thepresence of dicyclohexyl carbodiimide, with one molar equivalent of3-hydroxypyridine S36.16 to yield the mixed diester S36.17.

Using the above procedures, but employing, in place of the ethyl lactateS36.13 or 3-hydroxypyridine, a different hydroxyester S36.1 and/or adifferent hydroxy compound R³OH, the corresponding products S36.4 areobtained.

The mixed diesters S36.2 are also obtained from the monoesters S34.1 viathe intermediacy of the activated monoesters S36.5. In this procedure,the monoester S34.1 is converted into the activated compound S36.5 byreaction with, for example, phosphorus pentachloride, as described in J.Org. Chem., 2001, 66, 329, or with thionyl chloride or oxalyl chloride(Lv=Cl), or with triisopropylbenzenesulfonyl chloride in pyridine, asdescribed in Nucleosides and Nucleotides, 2000, 19, 1885, or withcarbonyl diimidazole, as described in J. Med. Chem., 2002, 45, 1284. Theresultant activated monoester is then reacted with the hydroxyesterS36.1, as described above, to yield the mixed diester S36.2.

The procedure is illustrated in Scheme 36, Example 3. In this sequence,a monophenyl phosphonate S36.9 is reacted, in acetonitrile solution at70° C., with ten equivalents of thionyl chloride, so as to produce thephosphoryl chloride S36.19. The product is then reacted with ethyl4-carbamoyl-2-hydroxybutyrate S36.20 in dichloromethane containingtriethylamine, to give the mixed diester S36.21.

Using the above procedures, but employing, in place of ethyl4-carbamoyl-2-hydroxybutyrate S36.20, different hydroxyesters S36.1, thecorresponding products S36.2 are obtained.

The mixed phosphonate diesters are also obtained by an alternative routefor incorporation of the R³⁰ group into intermediates S36.3 in which thehydroxyester moiety is already incorporated. In this procedure, themonoacid intermediate S36.3 is converted into the activated derivativeS36.6 in which Lv is a leaving group such as chloro, imidazole, and thelike, as previously described. The activated intermediate is thenreacted with the hydroxy compound R³OH, in the presence of a base, toyield the mixed diester product S36.4.

The method is illustrated in Scheme 36, Example 4. In this sequence, thephosphonate monoacid S36.22 is reacted with trichloromethanesulfonylchloride in tetrahydrofuran containing collidine, as described in J.Med. Chem., 1995, 38, 4648, to produce the trichloromethanesulfonyloxyproduct S36.23. This compound is reacted with 3-(morpholinomethyl)phenolS36.24 in dichloromethane containing triethylamine, to yield the mixeddiester product S36.25.

Using the above procedures, but employing, in place of with3-(morpholinomethyl)phenol S36.24, different alcohols R³OH, thecorresponding products S36.4 are obtained.

The phosphonate esters S36.4 are also obtained by means of alkylationreactions performed on the monoesters S34.1. The reaction between themonoacid S34.1 and the haloester S36.7 is performed in a polar solventin the presence of a base such as diisopropylethylamine, as described inAnal. Chem., 1987, 59, 1056, or triethylamine, as described in J. Med.Chem., 1995, 38, 1372, or in a non-polar solvent such as benzene, in thepresence of 18-crown-6, as described in Syn. Comm., 1995, 25, 3565.

The method is illustrated in Scheme 36, Example 5. In this procedure,the monoacid S36.26 is reacted with ethyl 2-bromo-3-phenylpropionateS36.27 and diisopropylethylamine in dimethylformamide at 80° C. toafford the mixed diester product S36.28.

Using the above procedure, but employing, in place of ethyl2-bromo-3-phenylpropionate S36.27, different haloesters S36.7, thecorresponding products S36.4 are obtained.

Scheme 37 illustrates methods for the preparation of phosphonatediesters in which both the ester substituents incorporate carboalkoxygroups.

The compounds are prepared directly or indirectly from the phosphonicacids S34.6. In one alternative, the phosphonic acid is coupled with thehydroxyester S37.2, using the conditions described previously in Schemes34-36, such as coupling reactions using dicyclohexyl carbodiimide orsimilar reagents, or under the conditions of the Mitsunobu reaction, toafford the diester product S37.3 in which the ester substituents areidentical.

This method is illustrated in Scheme 37, Example 1. In this procedure,the phosphonic acid S34.6 is reacted with three molar equivalents ofbutyl lactate S37.5 in the presence of Aldrithiol-2 and triphenylphosphine in pyridine at ca. 70° C., to afford the diester S37.6.

Using the above procedure, but employing, in place of butyl lactateS37.5, different hydroxyesters S37.2, the corresponding products S37.3are obtained.

Alternatively, the diesters S37.3 are obtained by alkylation of thephosphonic acid S34.6 with a haloester S37.1. The alkylation reaction isperformed as described in Scheme 36 for the preparation of the estersS36.4.

This method is illustrated in Scheme 37, Example 2. In this procedure,the phosphonic acid S34.6 is reacted with excess ethyl3-bromo-2-methylpropionate S37.7 and diisopropylethylamine indimethylformamide at ca. 80° C., as described in Anal. Chem., 1987, 59,1056, to produce the diester S37.8.

Using the above procedure, but employing, in place of ethyl3-bromo-2-methylpropionate S37.7, different haloesters S37.1, thecorresponding products S37.3 are obtained.

The diesters S37.3 are also obtained by displacement reactions ofactivated derivatives S34.7 of the phosphonic acid with thehydroxyesters S37.2. The displacement reaction is performed in a polarsolvent in the presence of a suitable base, as described in Scheme 36.The displacement reaction is performed in the presence of an excess ofthe hydroxyester, to afford the diester product S37.3 in which the estersubstituents are identical, or sequentially with limited amounts ofdifferent hydroxyesters, to prepare diesters S37.3 in which the estersubstituents are different.

The methods are illustrated in Scheme 37, Examples 3 and 4. As shown inExample 3, the phosphoryl dichloride S35.22 is reacted with three molarequivalents of ethyl 3-hydroxy-2-(hydroxymethyl)propionate S37.9 intetrahydrofuran containing potassium carbonate, to obtain the diesterproduct S37.10.

Using the above procedure, but employing, in place of ethyl3-hydroxy-2-(hydroxymethyl)propionate S37.9, different hydroxyestersS37.2, the corresponding products S37.3 are obtained.

Scheme 37, Example 4 depicts the displacement reaction between equimolaramounts of the phosphoryl dichloride S35.22 and ethyl2-methyl-3-hydroxypropionate S37.11, to yield the monoester productS37.12. The reaction is conducted in acetonitrile at 70° in the presenceof diisopropylethylamine. The product S37.12 is then reacted, under thesame conditions, with one molar equivalent of ethyl lactate S37.13, togive the diester product S37.14.

Using the above procedures, but employing, in place of ethyl2-methyl-3-hydroxypropionate S37.11 and ethyl lactate S37.13, sequentialreactions with different hydroxyesters S37.2, the corresponding productsS37.3 are obtained.

2,2-Dimethyl-2-aminoethylphosphonic acid intermediates can be preparedby the route in Scheme 5. Condensation of 2-methyl-2-propanesulfinamidewith acetone give sulfinyl imine S38.11 (J. Org. Chem. 1999, 64, 12).Addition of dimethyl methylphosphonate lithium to S38.11 afford S38.12.Acidic methanolysis of S38.12 provide amine S38.13. Protection of aminewith Cbz group and removal of methyl groups yield phosphonic acidS38.14, which can be converted to desired S38.15 (Scheme 38a) usingmethods reported earlier on. An alternative synthesis of compound S38.14is also shown in Scheme 38b. Commercially available2-amino-2-methyl-1-propanol is converted to aziridines S38.16 accordingto literature methods (J. Org. Chem. 1992, 57, 5813; Syn. Lett. 1997, 8,893). Aziridine opening with phosphite give S38.17 (Tetrahedron Lett.1980, 21, 1623). Reprotection) of S38.17 affords S38.14.

The invention will now be illustrated by the following non-limitingExamples.

Example 1

Rapamycin (compound, 1.1, wherein the remaining portion of the rapamycinstructure is not shown), a synthetic precursor of everolimus, isO-arylated as shown above using an appropriate aryl bismuth reagentaccording to a procedure such as that reported in Bioorg. Med. Chem.Lett, 1995, 5, 1035. 3-(Dimethyl-t-butylsilyloxy)bromobenzene is treatedeither with magnesium in diethyl ether or with butyllithium intetrahydrofuran, and the resulting organometallic reagent is reactedwith bismuth trichloride to generate the triarybismuthine. Aftertreating with 1-1.2 equivalents of peracetic acid, the bismuth(V)reagent is mixed with rapamycin and copper(II) acetate. The reaction isallowed to proceed for a day at room temperature or, if necessary, atreflux, affording the desired 3-(dimethyl-t-butylsilyloxy)phenyl ether,1.2. After removal of the dimethyl-t-butylsilyl protecting group,O-alkylation is achieved with diethyl (bromomethyl)phosphonate in thepresence of silver oxide, affording the desired everolimus analogcontaining the diethylphosphonate, 1.3. Silver ion-assisted reactionshave been used to mediate O-alkylations on an immunosuppresive macrolidestructurally similar to rapamycin: see J. Med. Chem., 1998, 41, 1764.

Example 2

A phosphonate derivative of everolimus indolyl ether is prepared fromrapamycin (formula, 2.1, wherein the remaining portion of the rapamycinstructure is not shown) in a similar manner to that described in Example1, with the exception that the key triindolylbismuthine intermediate isobtained from 5-bromoindole following the procedure described in J. Org.Chem. 1998, 63, 6721.

Example 3

Tacrolimus (compound, 3.1, wherein the remaining portion of thetacrolimus molecule is not shown) is O-arylated as shown above using anappropriate aryl bismuth reagent according to a procedure such as thatreported in Bioorg. Med. Chem. Lett, 1995, 5, 1035.3-(Dimethyl-t-butylsilyloxy)-bromobenzene is treated either withmagnesium in diethyl ether or with butyllithium in tetrahydrofuran, andthe resulting organometallic reagent is reacted with bismuth trichlorideto generate the triarybismuthine. After treating with 1-1.2 equivalentsof peracetic acid, the bismuth(V) reagent is mixed with tacrolimus, 3.1,and copper(II) acetate. The reaction is allowed to proceed for a day atroom temperature or, if necessary, at reflux, affording the desired3-(dimethyl-t-butylsilyloxy)phenyl ether. After removal of thedimethyl-t-butylsilyl protecting group with HF, O-alkylation is achievedwith diethyl (bromomethyl)phosphonate in the presence of silver oxide,affording the desired tacrolimus analog containing thediethylphosphonate, 3.3. Silver ion-assisted reactions have been used tomediate O-alkylations on an immunosuppresive macrolide structurallysimilar to tacrolimus. (See J. Med. Chem., 1998, 41, 1764.)

Example 4

A phosphonate derivative of, 4.3, tacrolimus indolyl ether is preparedfrom tacrolimus (compound, 4.1, wherein the remaining portion of thetacrolimus molecule is not shown) in a similar manner to that describedin Example 3 with the exception that the key triindolylbismuthineintermediate is obtained from 5-bromoindole following the proceduredescribed in J. Org. Chem. 1998, 63, 6721.

Example 5

Representative compounds of the invention can be made by procedures suchas those described by Boer, et al, J. Mass Spectrom. 1995, 30, 497-504and Hoyte, et al, J. Med. Chem. 2002, 45, 5397-5405; they can also bemade according to the following general routes.

Compounds of formulae, 5.1 and 5.2, wherein “Link” have any of thevalues defined herein for a linking group or a linker, arerepresentative compounds of the invention.

Example 6

Prednisolone, 6A, is treated in a solvent, such as chloroform, withformaldehyde in the presence of an acid, such as concentratedhydrochloric acid. After stirring for several hours (preferably 7 to 10hours) at room temperature, the layers are separated and the organiclayer is concentrated to afford the bis-(methylenedioxy) intermediate,5.3 (Hirschmann, R. et al, J. Am. Chem. Soc. 1964, 86, 1520-1527). Thisintermediate is treated with diethyl (amino-oxymethyl)phosphonate in asolvent such as pyridine to afford the oxime, 5.4. The oxime is treatedwith aqueous acid to remove the bis-(methylenedioxy) protecting group.For example, the oxime is treated with 60% aqueous formic acid andheated at 90° C. for 10 min., cooled and concentrated using portions ofethanol to assist in removing formic acid. Chromatographic purificationand/or crystallization of the residue yield the phosphonate oximeanalog, 5.5, of prednisolone.

A key precursor of this synthesis, diethyl (aminooxymethyl)phosphonate,can be obtained from diethyl(trifluoromethyl-sulfonyloxymethyl)phosphonate andN-(t-butoxycarbonyl)-hydroxylamine. Accordingly,N-(t-butoxycarbonyl)-hydroxylamine is dissolved in a solvent such as THFand treated with sodium hydride. When bubbling ceases, diethyl(trifluoromethylsulfonyloxymethyl)-phosphonate (prepared according toTetrahedron Lett., 1986, 27, 1477) is added. After quenching thereaction with aqueous ammonium chloride and extracting the product withan organic solvent such as ethyl acetate, the N-Boc protected diethyl(aminooxymethyl)phosphonate is isolated by chromatography. The N-Bocprotecting group is then removed by treatment of trifluoroacetic acid,affording the desired diethyl (aminooxymethyl)phosphonate.

Example 7

Prednisolone, 6A, is reduced to 1,2-dihydroprednisolone, 7.1, using arhodium catalysis such as tris(triphenylphosphine)rhodium(I) chlorideunder hydrogen according to a procedure such as that reported byProcopiou, P. et al, J. Med. Chem., 2001, 44, 602-612. The dihydroxyketone group on the D ring of the steroid is then protected using themethod described in Example 6, before formylation at the C-2 position.For example, the bis-(methylenedioxy) intermediate, 7.2, is treated withfreshly distilled ethyl formate and sodium hydride in a solvent such astoluene. The reaction is quenched with aqueous solution of a weak basesuch as potassium dihydrogen phosphate. The crude product is purified bya general method such as crystallization, affording the 2-formylintermediate, 7.3. This 2-formyl compound is condensed with aphosphonate-substituted phenylhydrazine to yield, after removal of thebis-(methylenedioxy) protecting group, the desired phosphonate pyrazoleanalog, 7.4, of prednisolone.

A key precursor, 3-[(diethylphosphono)-methoxy]phenylhydrazine, 7.5, canbe made starting from diethyl(trifluoromethylsulfonyloxymethyl)-phosphonate and 3-nitrophenol.3-Nitrophenol is treated with a base such as sodium hydroxide and thenO-alkylated with diethyl (trifluoromethylsulfonyl-oxymethyl)phosphonate.The nitro group is reduced with tin(II) chloride and subsequentlyconverted to the aryl hydrazine by diazotization and reduction withsodium sulfite (Chem. Ber., 1960, 93, 540) or tin(II) chloride (J. Med.Chem., 2001, 44, 4031).

Examples 8-13

Synthetic methodologies and intermediate compounds that can be used toprepare VX-148 analogs of formulae A, B, or C are described in Examples8-13. The below compounds are representative examples of compounds ofFormulae 6, 7, and 8.

Link includes 0-8 atoms; 2-6 is preferred.

Example 8

A general scheme that is useful for converting a 3,5-difunctionalizednitrobenzene derivative to an aniline that can be used to prepare aVX-148 analog of the invention is illustrated above.

Example 9

3-Hydroxy-5-nitro-benzoic acid is heated briefly in thionyl chloride togenerate the acid chloride. The acid chloride is condensed withO,N-dimethyl-hydroxylamine in the presence of a base such astriethylamine to produce the Weinreb amide which, upon reaction withmethyl lithium, provides the acetophenone derivative. The acetophenonederivative is treated with a base such as potassium carbonate in adipolar aprotic solvent such as dimethyl-formamide, in the presence ofan excess of E-1,4-dibromobutene. The monobromide is isolated bychromatography and then subjected to treatment with triethylphosphite ina solvent such as toluene (or other Arbuzov reaction conditions: seeEngel, R., “Synthesis of Carbon-phosphorus Bonds,” CRC press, 1988) togenerate the desired phosphonate diethyl ester. Thereafter, the carbonylof the acetophenone is reduced enantioselectively using an appropriatehomochiral oxazaborolidine such as that described by Corey (J. Am. Chem.Soc., 1987, 109, 5551), and the resulting alcohol is displaced by azideusing a method such as that described by Mitsunobu (Bull. Chem. Soc.Japan., 1971, 44, 3427). The azide is reduced to the amine underStaudinger conditions (Helv. Chim. Act., 1919, 2, 635) and protected asthe t-butyl carbonate. Finally, the desired aniline intermediate isgenerated by tin (II)-mediated reduction of the nitrobenzene. Theaniline is converted to a compound of Formula A (also Formula 6) usingcoupling reactions similar to those described in U.S. Pat. No. 6,054,472and U.S. Pat. No. 6,344,465.

Example 10

A general scheme that is useful for converting a 3,4-difunctionalizednitrobenzene derivative, 10.1, to an aniline, which can be converted toa compound of Formula B (also Formula 7) using coupling reactionssimilar to those described in U.S. Pat. No. 6,054,472 and U.S. Pat. No.6,344,465, is illustrated above.

Example 11

Manipulation of a 3-substituted nitrobenzene, 11.1, provides aniline,11.2, which can be converted to a compound of formula C (also Formula 8)using coupling reactions similar to those described in U.S. Pat. No.6,054,472 and U.S. Pat. No. 6,344,465.

Example 12

3-Nitrobenzaldehyde, 12.1, reacts with a Grignard reagent to introduce atether bearing a protected alcohol and simultaneously to generate abenzylic alcohol, as shown. The alcohol, 12.2, is displaced by an azidein a manner similar to that described for Example 9. After deprotection,the liberated alcohol is alkylated with diethyl phosphonomethyltriflate(prepared according to Tetrahedron Lett., 1986, 27, 1477) using a basesuch as magnesium tert-butoxide in a solvent such as tetrahydrofuran.Subsequent transformations of the azide and nitro groups proceed in afashion similar to that described in Example 9. See Batt et al, Bioorg.Med. Chem. Lett., 1995, 5, 1549.

Example 13

3-tert-Butoxycarbonylamino-3-(3-nitro-phenyl)-propionic acid, 13.1,(commercially available) is coupled with 2-aminoethylphosphonic aciddiethyl ester (commercially available) using standard reagents for theformation of a secondary amide such as dicyclohexylcarbodiimide (DCC)and hydroxy-benztriazole (HOBT), in a solvent such as dimethylformamide.Subsequent reduction of the nitro group proceeds in a fashion similar tothat described in Example 9.

Example 14

The above scheme illustrates a general route that can be used to preparecompounds of Formula 9.

Example 15

3-Hydroxy-5-nitro-benzoic acid, 15.1, is heated briefly in thionylchloride to generate the acid chloride. This is then condensed withO,N-dimethyl-hydroxylamine in the presence of a base such astriethylamine to produce the Weinreb amide which, upon reaction withmethyl lithium, gives the acetophenone derivative. This is then treatedwith a base such as potassium carbonate in a dipolar aprotic solventsuch as dimethyl-formamide, in the presence of an excess ofE-1,4-dibromobutene. The monobromide is isolated by chromatography andthen subjected to treatment with triethylphosphite in a solvent such astoluene (or other Arbuzov reaction conditions: see Engel, R., “Synthesisof Carbon-phosphorus Bonds,” CRC press, 1988) to generate the desiredphosphonate diethyl ester, 15.2. Thereafter, the carbonyl of theacetophenone is reduced enantioselectively using an appropriatehomochiral oxazaborolidine such as that described by Corey (J. Am. Chem.Soc., 1987, 109, 5551), and the resulting alcohol is displaced by azideusing a method such as that described by Mitsunobu (Bull. Chem. Soc.Japan., 1971, 44, 3427). The azide is reduced to the amine underStaudinger conditions (Helv. Chim. Act., 1919, 2, 635) and protected asthe t-butyl carbonate. Finally, the desired aniline intermediate, 15.3,is generated by tin (II)-mediated reduction of the nitrobenzene.

Example 16

Reagents suitable for use in the synthesis of representative compoundsof Formula 10 may be made by routes analogous to that shown in Example10, starting from 2-hydroxy-5-nitro-benzoic acid.

Example 17

Representative compounds of Formula 11 can be prepared as illustrated inExamples 11-13, above. The preparation of anilines of formula, 17.2, isillustrated in Examples 11-13 above. Anilines of formula, 17.2, can beconverted to compounds of Formula 11 using procedures similar to thosedescribed in U.S. Pat. No. 6,054,472 and U.S. Pat. No. 6,344,465.

Example 18

The following is a general route that can be used to prepare compoundsof Formula 15.

Example 19

The initial Pfitzinger condensation of compound 19.1 and compound 19.2is achieved in a single step using potassium hydroxide with acidicwork-up, as shown. Alternatively, the initial aldol condensation may beperformed using diethylamine in ethanol, and the quinoline ring may beformed in a second step mediated by an acid such as hydrochloric acid ina solvent such as 1,4-dioxane. Following removal of the benzylprotecting group via hydrogenation, the phenol can be treated in asolvent such as tetrahydrofuran or dimethylformamide with a base such assodium hydride. When bubbling ceases, diethyl phosphonomethyltriflate(prepared according to Tetrahedron Lett., 1986, 27, 1477) is added,yielding the desired phosphonate diester. The carboxylate is deprotectedby treatment with lithium hydroxide in ethanol to provide compound 19.4(which is a compound of Formula 12).

Example 20

The synthesis is similar to that depicted in Example 19 except that,following deprotonation of the phenol, E-1,4-dibromobutene is added inexcess. After quenching the reaction with aqueous ammonium chloride andextracting the product with an organic solvent such as ethyl acetate,the mono-alkylated product is isolated by chromatography. The resultingbromide is heated with triethylphosphite in a solvent such as toluene togenerate the diethyl ester of the desired phosphonic acid, and thecarboxylic acid is deprotected as before to provide compound 20A (whichis a compound of Formula 12).

Example 21

The structures of Prednisone, 21A (U.S. Pat. No. 2,897,464), andrepresentative phosphonate esters are shown below, in which thesubstituent R¹ is H, alkyl, alkenyl, aryl or aralkyl. The phosphonatecompounds incorporate a phosphonate moiety (R¹O)₂P(O) connected to thenucleus by means of a variable linking group, designated as “link.”

For example, the above scheme depicts a protection-deprotection sequencein which the steroid side-chain is protected as a bis-methylenedioxy(BMD) moiety. In this sequence, Prednisone, 21A, is reacted withparaformaldehyde and an acid catalyst such as hydrochloric acid, asdescribed in “Protective Groups in Organic Synthesis,” by T. W. Greeneand P. G. M. Wuts, Wiley, Second Edition 1990, p. 223, to yield the BMDderivative, 21.1. The phosphonate moiety is then introduced, using theprocedures described below, to produce the phosphonate ester, 21.2. TheBMD moiety is then hydrolyzed, for example by treatment with 50% aqueousacetic acid, as described in “Protective Groups in Organic Synthesis,”by T. W. Greene and P. G. M. Wuts, Wiley, Second Edition 1990, p. 223,to afford the triol, 21.3 (which is a compound of Formula 23).

Optionally, depending on the nature of the reactions employed, the1-ketone group in the BMD compound, 21.1, is protected beforeintroduction of the phosphonate group. The ketone is protected, forexample, as the cyclic ethylene ketal, by reaction in toluene solutionat reflux temperature with ethylene glycol and an acid catalyst, asdescribed in J. Am. Chem. Soc., 1955, 77, 1904. Deprotection is effectedby reaction with pyridinium tosylate in aqueous-acetone, as described inJ. Chem. Soc., Chem. Comm., 1351, 1987.

Alternatively, the 11-ketone is protected by conversion to theN,N-dimethylhydrazone. The dimethyl hydrazone is prepared by thereaction of the ketone, 21.1, with N,N-dimethylhydrazine inethanol-acetic acid, as described in Org. Syn., 1970, 50, 102. The groupis removed by treatment with sodium acetate and acetic acid in aqueoustetrahydrofuran, as described in J. Am. Chem. Soc., 1979, 101, 5841.

Alternatively, the 11-ketone is protected as the diethylamine adduct. Inthis procedure, the substrate, 21.1, is reacted with titaniumtetrakis-(diethylamide), as described in J. Chem. Soc., Chem. Comm.,406, 1983, to afford the adduct. The ketone is deprotected by reactionwith water in an aqueous organic solvent.

The 11-protected BMD compound, 21.4, is then converted, using theprocedures described below, into the phosphonate, 21.5. Deprotectionthen yields the 11-keto diol, 21.3.

Example 22

The preparation of phosphonates, 22.3, in which the phosphonate isattached by means of an imino or iminoxy group and a variable carbonchain are depicted above. In this procedure, the doubly-protectedderivative, 21.4, is reacted with an amine or hydroxylamine, 22.1, inwhich R² is an alkyl, alkenyl, cycloalkyl or cycloalkenyl group,optionally incorporating a heteroatom O, S or N, or a functional groupsuch as an amide, ester, oxime, sulfoxide or sulfone etc, or anoptionally substituted aryl, heteroaryl or aralkyl group, optionallyincorporating a heteroatom O, S or N, and X is either a phosphonategroup or a group which is subsequently converted into aphosphonate-containing substituent.

For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxy andthe like. The reaction is conducted between equimolar amounts of thereactants in an aprotic solvent such as pyridine or xylene, or in analcoholic solvent such as ethanol, optionally in the presence of an acidcatalyst, to give the imine or oxime. The preparation of oximes ofsteroidal 3-ketones is described in Anal. Bioch., 1978, 86, 133 and inJ. Mass. Spectrom., 1995, 30, 497. The protecting groups are thenremoved to afford the ketodiol, 22.3 (which is a compound of Formula16).

Example 23

The preparation of phosphonates, P2.10, in which the phosphonate isattached by means of an iminoxy group, is illustrated above. Thesubstrate, 23.1, a compound of Formula 23.1, in which the 11-ketone isprotected as the dimethyl hydrazone, is reacted with a dialkylphosphonomethyl hydroxylamine, P2.8, prepared from a dialkyltrifluoromethyl-sulfonyloxymethyl phosphonate (Tetrahedron Lett., 1986,27, 1477) and BOC-hydroxylamine, to afford the oxime, P2.9, which isdeprotected by reaction with 50% aqueous acetic acid, to afford thediol, P2.10. The oxime forming reaction is typically performed atambient temperature in ethanol-acetic acid solution between equimolaramounts of the reactants.

The intermediate dialkyl phosphonomethyl hydroxylamine, P2.8, (compound,2.7, wherein R² is a bond) can be prepared as follows.

A phosphonate, P2.4, in which Lv is a leaving group such as bromo ortrifluoromethylsulfonyloxy, is reacted with BOC-hydroxylamine, P2.5,(Aldrich) to produce the ether, P2.6. The reaction is typicallyconducted between equimolar amounts of the reactants in a polar solventsuch as dimethyl-formamide or tetrahydrofuran, in the presence of a basesuch as potassium hydroxide or dimethylaminopyridine. Deprotection, forexample, by treatment with trifluoroacetic acid, then gives thehydroxylamine ether, P2.7.

Example 24

The dienone, 23.1, is reacted, as described in Example 23, withO-(2-bromobenzyl)hydroxylamine, P2.11, prepared from 2-bromobenzylbromide, to give, after deprotection, the oxime, P2.12. The product isthen reacted, in the presence of a palladium catalyst, with a dialkylphosphite, P2.13, to afford the phosphonate, P2.14. The preparation ofarylphosphonates by means of a coupling reaction between aryl bromidesand dialkyl phosphites is described in J. Med. Chem., 1992, 35, 1371.The reaction is typically performed in an inert solvent such as toluene,in the presence of a base such as triethylamine and a catalytic amountof tetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo compound, P2.12, is coupled with a dialkylvinylphosphonate, P2.15 (Aldrich), to afford the phosphonate, P2.16. Thecoupling of aryl halides with olefins by means of the Heck reaction isdescribed, for example, in “Advanced Organic Chemistry,” by F. A. Careyand R. J. Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem. Ras., 1979,12, 146. The aryl bromide and the olefin are coupled in a polar solventsuch as dimethyl-formamide or dioxan, in the presence of a palladium(0)catalyst such as tetrakis(triphenylphosphine)palladium(0) orpalladium(II) catalyst such as palladium(II) acetate, and optionally inthe presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product, P2.16, isreduced, for example by reaction with diimide, to produce the saturatedanalog, P2.17. The reduction of olefinic bonds is described in“Comprehensive Organic Transformations,” by R. C. Larock, VCH, 1989, p.6ff. The transformation is effected by means of catalytic hydrogenation,for example using a palladium on carbon catalyst and hydrogen or ahydrogen donor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of the benzyloxyreagent, P2.11, different bromo-substituted aryl or heteroaryl alkoxyhydroxylamines, and/or different dialkyl alkenyl phosphonates, theproducts analogous to the compounds, P2.14, P2.16 and P2.17 areobtained.

Example 25

The preparation of phosphonates of Formula 16 wherein the phosphonate isattached by means of an imino group is illustrated above. The substrate,23.1, is reacted with a dialkyl 4-aminophenyl phosphonate, P2.18(Epsilon), to give, after deprotection, the imine product, P2.19. Thereaction is typically conducted in a hydrocarbon solvent such as tolueneor xylene, at reflux temperature, in the presence of a basic catalystsuch as sodium methoxide, or an acid catalyst such as p-toluenesulfonicacid, under azeotropic conditions.

Example 26

The preparation of representative phosphonates of Formula 16 wherein thephosphonate is attached by means of an oximino group and an etherlinkage is illustrated above. In this procedure, the dienone, 23.1, isreacted with O-(2-hydroxyyethyl)hydroxylamine, P2.20 (J. Chem. Soc.,Chem. Comm., 1986, 903), to yield the oxime, P2.21. The reaction ofsteroidal 1,4-dien-3-ones with substituted hydroxylamines is describedin J. Steroid Bioch., 1976, 7, 795. The reaction is performed betweenequimolar amounts of the reactants in a polar organic solvent such aspyridine or methanol, optionally in the presence of acetic acid orsodium acetate. The oxime is then reacted in a Mitsonobu reaction with adialkyl 4-hydroxyphenyl phosphonate, P2.22 (Epsilon), to yield the etheroxime, P2.23. The preparation of aromatic ethers by means of theMitsonobu reaction is described, for example, in “Comprehensive OrganicTransformations,” by R. C. Larock, VCH, 1989, p. 448, and in “AdvancedOrganic Chemistry,” Part B, by F. A. Carey and R. J. Sundberg, Plenum,2001, p. 153-4 and in Org. React., 1992, 42, 335. The phenol and thealcohol or thiol component are reacted together in an aprotic solventsuch as, for example, tetrahydrofuran, in the presence of a dialkylazodicarboxylate and a triarylphosphine, to afford the ether orthioether products. The procedure is also described in Org. React.,1992, 42, 335-656. The ether product, P2.23. is then converted into theketodiol, P2.24 (which is a compound of Formula 16).

Using the above procedures, but employing, in place of thehydroxylamine, P2.20, different hydroxy-substituted hydroxylamines,and/or different hydroxy-substituted aryl phosphonates, the productsanalogous to P2.24 are obtained.

Example 27

The preparation of the phosphonate esters of Formulae 17 and 18 in whichthe phosphonate group is attached to the 1′ or 2′ position of thepyrazole ring, by means of an aromatic or heteroaromatic group, aheteroatom and a variable carbon chain. In this procedure, theBMD-protected dienone, 21.1, is reduced to afford the 1,2-dihydroproduct, P3.1. The catalytic hydrogenation reaction is effected by theuse of tris(triphenylphosphine)rhodium (I) chloride, for example asdescribed in J. Med. Chem., 2001, 44, 602. The product is then reactedwith ethyl formate and a base such as sodium hydride, in an inertsolvent such as toluene or dimethylformamide, as described in J. Am.Chem. Soc., 1964, 86, 1520, to afford the 2-formyl product, P3.2. Thiscompound is then reacted with an alkyl, aralkyl, aryl or heteroarylhydrazine, P3.3, in which the substituent X is either a phosphonategroup or a group which is subsequently transformed into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxyl and the like. The reaction yields theisomeric 2′- and 1′-aryl pyrazoles, P3.4 and P3.5. The pyrazole-formingreaction is performed between equimolar amounts of the reactants in anacidic solvent such as acetic acid, as described in J. Am. Chem. Soc.,1964, 86, 1520. The pyrazoles, P3.4 and P3.5, are then transformed viathe BMD-protected intermediates, P3.6 and P3.7, into the phosphonates,P3.8 and P3.9, which are compounds of Formulae 17 and 18 respectively.

Example 28

The preparation of phosphonates in which the phosphonate is attached bymeans of a phenyl ring and an ester or an amide linkage are illustratedabove. The ketoaldehyde, P3.2, is reacted with 3-carboxyphenylhydrazine,P3.10 (Apin), to give the pyrazoles, P3.11 and P3.12. The 2′-substitutedisomer, P3.11, is then reacted in dichloromethane solution at ambienttemperature with one molar equivalent of a dialkyl2-hydroxy-2-methylpropyl phosphonate, P3.13 (French Patent No.2,462,440), and dicyclohexylcarbodiimide, to yield the ester, P3.14. Theprotecting groups are then removed to yield the diol, P3.15, which is acompound of Formula 18.

Alternatively, the 1′-substituted pyrazole, P3.12, is coupled with adialkyl 2-aminoethyl phosphonate, P3.17 (Aurora), to afford the amide,P3.18. The preparation of amides from carboxylic acids and derivativesis described, for example, in “Organic Functional Group Preparations,”by S. R. Sandler and W. Karo, Academic Press, 1968, p. 274, and“Comprehensive Organic Transformations,” by R. C. Larock, VCH, 1989, p.972ff. The carboxylic acid is reacted with the amine in the presence ofan activating agent, such as, for example, dicyclohexylcarbodiimide ordiisopropylcarbodiimide, optionally in the presence of, for example,hydroxybenztriazole, N-hydroxy-succinimide or N-hydroxypyridone, in anon-protic solvent such as, for example, pyridine, DMF ordichloromethane, to afford the amide.

Alternatively, the carboxylic acid may first be converted into anactivated derivative such as the acid chloride, anhydride, mixedanhydride, imidazolide and the like, and then reacted with the amine, inthe presence of an organic base such as, for example, pyridine, toafford the amide. The conversion of a carboxylic acid into thecorresponding acid chloride can be effected by treatment of thecarboxylic acid with a reagent such as, for example, thionyl chloride oroxalyl chloride in an inert organic solvent such as dichloromethane,optionally in the presence of a catalytic amount of dimethylformamide.The product, P3.18, is then deprotected to give the diol, P3.19 (whichis a compound of Formula 17).

Using the above procedures, but employing different amino orhydroxyl-substituted phosphonates, and/or different carboxy-substitutedhydrazines, the products analogous to P3.15 and P3.19 are obtained. Thefunctionalization procedures are interchangeable between the pyrazolesubstrates, P3.11 and P3.12.

Example 29

The preparation of the phosphonates of Formulae 17 and 18 wherein thephosphonate group is attached by means of a phenyl group and an alkoxyor alkylthio carbon chain is illustrated above. In this procedure, theketoaldehyde, P3.2, is reacted with 4-hydroxyphenyl hydrazine, P3.20 (EP437 105), to produce the pyrazoles, P3.21 and P3.22. The 1′-substitutedisomer, P3.21, is reacted, in dimethylformamide solution at 70′, with adialkyl bromopropyl phosphonate, P3.23 (J. Amer. Chem. Soc., 2000, 122,1554), and potassium carbonate, to give the phosphonate, P3.24. Theproduct is then deprotected to afford the diol, P3.25.

Alternatively, the 2′-substituted pyrazole, P3.22, is reacted in aMitsonobu reaction, as described above, with a dialkyl mercaptoethylphosphonate, P3.26 (Zh. Obschei. Khim., 1973, 43, 2364), to prepare thethioether phosphonate, P3.27, which is deprotected to give the diol,P3.28.

Using the above procedures, but employing, in place of the hydroxyphenylreagent, P3.20, different hydroxy-substituted aralkyl, aryl orheteroaryl alkoxy hydrazines, and/or different dialkyl bromo ormercapto-substituted phosphonates, the products analogous to thecompounds, P3.25 and P3.28 are obtained.

Example 30

The preparation of phosphonate esters of Formulae 17 and 18 wherein thephosphonate group is attached by means of a variable carbon linkage isillustrated above. In this procedure, the ketoaldehyde, P3.2, is reactedwith hydrazine to afford the pyrazole derivative, P4.1. The reaction ofsteroidal 2-formyl-3-ketones with hydrazine is described in J. Am. Chem.Soc, 1964, 86, 1520. The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound, P4.2, to yield the alkylation products, P4.3 and P4.4. Thealkylation of substituted pyrazoles is described, for example, in“Heterocyclic Chemistry,” by T. L. Gilchrist, Longman, 1992, p. 309. Thereaction is typically performed between equimolar amounts of thesubstrates in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts, P4.3 and P4.4, are, except in cases where X isdialkylphosphono, converted into the phosphonates, P4.5 and P4.6, usingthe procedures described herein. Deprotection affords the diols, P4.7and P4.8 (which are compounds of Formulae 18 and 17, respectively).

Example 31

As illustrated above, the pyrazole, P4.1, is reacted with one molarequivalent of a dialkyl trifluoromethanesulfonyloxy phosphonate, P4.9,as described above to give the alkylated pyrazoles, P4.10 and P4.11.Deprotection yields the diols, P4.12 and P4.13 (which are compounds ofFormulae 18 and 17 respectively).

Example 32

As illustrated above, the pyrazole, P4.1, is reacted, as describedabove, with 1,4-bis(bromomethyl)cyclohexane, P4.14 (Salor), to give thepyrazoles, P4.15 and P4.16. The product, P4.15, is subjected to anArbuzov reaction, in which the bromomethyl substituent is converted intothe dialkyl phosphonomethyl substituent, by reaction with a trialkylphosphite to prepare, after deprotection of the side chain, thephosphonate, P4.17, (which is a compound of Formula 18).

The pyrazole, P4.16, is reacted in dimethylformamide with potassiumcarbonate and a dialkyl aminomethyl phosphonate, P4.18, (Interchim) togive after deprotection the amino phosphonate, P4.19, which is acompound of Formula 17.

Using the above procedures, but employing, in place of the dibromide,P4.14, different dibromides, and/or different amino-substitutedphosphonates, the products analogous to P4.17 and P4.19 are obtained.

Example 33

Representative compounds of the invention can be prepared as generallydescribed by Westwood et al, J. Med. Chem., 1996, 39, 4608-4621, andaccording to the following general route.

Coupling of a suitable aniline, 33.1, wherein X¹ is hydrogen, halo,trifluoromethyl, (C₁-C₃)alkyl, cyano, or (C₁-C₃)alkoxy, with acidchloride, 33.2, provides compound, 33.3 (which is a representativecompound of Formula 19 or 20).

The synthesis of two suitable anilines that can be employed in the abovereaction is outlined below.

3-Nitrophenol is alkylated with E-1,4-dibromobutene and the resultingmonobromide is heated with triethylphosphite in a solvent such astoluene (or other Arbuzov reaction conditions to generate the diethylester of the desired phosphonic acid, 33.4. (See Engel, R., “Synthesisof Carbon-phosphorus Bonds,” CRC press, 1988). Finally, the desiredaniline is generated by tin (II)-mediated reduction of the nitrobenzene.

The methyl ester of 3-nitro-4-trifluoromethylbenzoic acid is treatedwith tin (II) chloride to produce the corresponding aniline. The3-iodobenzoic acid is generated by diazotization and treatment withpotassium iodide. A diethylphosphonate ester is attached via anacetylene linker using palladium catalysis, and after saponification ofthe benzoate ester, Curtius rearrangement of the acyl azide provides ananiline suitable for incorporation into representative MNA-715 analogsof the invention.

Example 34

Representative compounds of Formulae 21 and 22 can be prepared asgenerally described by Westwood et al, J. Med. Chem., 1996, 39,4608-4621, and according to the following general route.

Coupling of a suitable aniline, 34.1, wherein X² is hydrogen, halo,trifluoromethyl, cyano, or methyl with acid chloride, 34.2, provides arepresentative compound of Formulae 21 and 22. Anilines prepared asdescribed in Example 33 and elsewhere herein can be incorporated intothis synthesis.

Example 35

5-Nitro-isobenzofuran-1,3-dione, 35.1, (commercially available), isconverted to 5-amino-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione,35.2, following the procedures reported in Bioorg. Med. Chem. Lett.,1999, 9, 1625. This amine intermediate is subjected to a reductiveamination with diethyl-phosphonoacetaldehyde (obtained from ozonolysisof diethyl allyphosphonate) in the presence of a reducing agent such assodium triacetoxyborohydride to generate the desired amine linker analog(J. Org. Chem., 1996, 61, 3849). Alternatively, the amine is acylatedwith an activated diethylphosphonoacetic acid to provide the desiredamide linker compound, according to a procedure such as those reportedin J. Med. Chem., 1982, 25, 960 and J. Med. Chem., 1984, 27, 600. Theactivated diethylphosphonoacetic acid can be obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature. A specific example where X is CH₂ is illustratedbelow.

Alternatively, 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pentanedioicacid, 35.4, (commercially available) is treated in a solvent such asacetonitrile with triethylamine, 1-hydroxybenzotriazole,4-methoxybenzylamine, and 1,3-dicyclohexylcarbodiimide. After thereaction is complete, the solvent is removed and the residue is purifiedby chromatography to generate the desired analog, 35.3, according to aprocedure such as that reported in J. Med. Chem., 2003, 46, 3793.

Example 36

The Boc-protected(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol, compound,36.3, is prepared by stirring the(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol (WO 99/19338and Evans, G. B. et al., Tetrahedron, 2000, 56, 3053, also reported inEvans, G. B. et al., J. Med. Chem. 2003, 46, 3412) with BOC anhydride asdescribed in Greene, T., “Protective groups in organic synthesis,”Wiley-Interscience, 1999. Compound, 36.3, is then treated in a solventsuch as tetrahydrofuran or dimethylformamide with a base such as sodiumhydride. When bubbling ceases, diethyl phosphonomethyl-triflate(prepared according to Tetrahedron Lett., 1986, 27, 1477) is added,yielding the desired phosphonate diester, 36.4, after deprotection ofthe BOC group using trifluoroacetic acid (TFA) (which is a compound ofFormula 25).

Example 37

Protected compound, 37.1,((1R)-1-(9-deazahypoxanthin-9-yl)-1,2,4-trideoxy-1,4-imino-D-erythro-pentitol,as the hydrochloride salt) is prepared as described in Evans, G. B. etal., Tetrahedron, 2000, 56, 3053, using di-t-butyl dicarbonate indichloromethane. Oxidation of the 5′-OH followed by elimination providesglycal, 37.3 (see the procedure of Zemlicka J. et al., J. Am. Chem.Soc., 1972, 94, 9, 3213). Selenoetherification provides the protectedphosphonate, 37.4 (Kim, C. et al., J. Org. Chem., 1991, 56, 2642).Oxidative elimination of the phenylselenide (as described in Kim, C. etal., J. Org. Chem., 1991, 56, 2642) followed by stereoselectivedihydroxylation provides the desired diol, 37.6. Finally, the protectinggroup is removed to provide a compound, 37.7, compound of Formula 26.

Example 38

(1R)-1-(9-Deazahypoxanthin-9-yl)-1,2,4-trideoxy-1,4-imino-D-erythro-pentitol,prepared as the HCl salt as described in Evans, G. B. et al.,Tetrahedron, 2000, 56, 3053, is first protected and then oxidized withPtO₂ to provide carboxylic acid, 38.1. Decarboxylative elimination isachieved using dimethylformamide dineopentyl acetal in dimethylformamideat high temperature (Zemlicka J. et al., J. Am. Chem. Soc., 1972, 94, 9,3213). Selenoetherification followed by treatment of the protectedglycal with silver perchlorate in the presence ofdiethyl(hydroxylmethyl)phosphonate (Phillion, D. et al., TetrahedronLett., 1986, 27, 1477) provides the phosphonate, 38.3 (Kim, C. et al.,J. Org. Chem., 1991, 56, 2642). Oxidative elimination of the selenidefollowed by dihydroxylation using osmium tetraoxide provides diol, 38.5.Removal of the amine protecting group, according to the procedure ofGreene, T., “Protective groups in organic synthesis,”Wiley-Interscience, 1999, provides compound 38.6.

Example 39

Synthetic methodologies and intermediate compounds that can be used toprepare pro-drugs of analogs of thalidomide are described below.

-   -   link includes 1 or more atoms; 2 or more is preferred

2-Methyl-4-nitrobenzoic acid methyl ester (commercially available) isconverted to3-(5-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione, 39.1,following the procedures reported in Bioorg. Med. Chem. Lett., 1999, 9,1625. This amine intermediate is subjected to a reductive amination withdiethylphosphonoacetaldehyde (obtained from ozonolysis of diethylallyphosphonate) in the presence of a reducing agent such as sodiumtriacetoxyborohydride to generate the desired amine linker analog, 39.2(J. Org. Chem., 1996, 61, 3849). Alternatively, the amine is acylatedwith an activated diethylphosphonoacetic acid to provide the desiredamide linker compound, 39.3, according to a procedure such as thosereported in J. Med. Chem., 1982, 25, 960 and J. Med. Chem., 1984, 27,600. The activated diethylphosphono-acetic acid can be obtained bytreatment, in a solvent such as dimethylformamide, with a couplingreagent such as diethyl cyanophosphonate and a base such asdiisopropylethylamine at room temperature.

2-Methyl-3-nitrobenzoic acid methyl ester (commercially available) istreated in a solvent such as carbon tetrachloride withN-bromosuccinimide under light to produce 2-bromomethyl-3-nitrobenzoicacid methyl ester, 39.4. The benzylic bromide is treated in a solventsuch as dimethylformamide with[2-(3-amino-2,6-dioxo-piperidin-1-yl)-ethyl]-phosphonic acid diethylester (for the preparation of this compound, see Example 40, below) inthe presence of a base such as triethylamine. The coupled product isthen reduced by hydrogenation (Bioorg. Med. Chem. Lett., 1999, 9, 1625)to afford the desired analog.

Example 40

2-Methyl-4-nitrobenzoic acid methyl ester, 39.2 (commerciallyavailable), is converted to3-(5-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione,following the procedures reported in Bioorg. Med. Chem. Lett., 1999, 9,1625. This amine intermediate is subjected to a reductive amination withdiethylphosphonoacetaldehyde (obtained from ozonolysis of diethylallyphosphonate) in the presence of a reducing agent such as sodiumtriacetoxyborohydride to generate the desired amine linker analog (J.Org. Chem., 1996, 61, 3849). Alternatively, the amine is acylated withan activated diethylphosphonoacetic acid to provide the desired amidelinker compound, according to a procedure such as those reported in J.Med. Chem., 1982, 25, 960 and J. Med. Chem., 1984, 27, 600. Theactivated diethylphosphonoacetic acid can be obtained by treatment in asolvent such as dimethylformamide with a coupling reagent such asdiethyl cyanophosphonate and a base such as diisopropylethylamine atroom temperature.

Example 40A

2-Methyl-3-nitrobenzoic acid methyl ester, 39.2 (commercially available)is treated in a solvent such as carbon tetrachloride withN-bromosuccinimide under light to produce 2-bromomethyl-3-nitrobenzoicacid methyl ester, 39.4. This benzylic bromide is treated in a solventsuch as dimethylformamide with[2-(3-amino-2,6-dioxo-piperidin-1-yl)-ethyl]-phosphonic acid diethylester (for the preparation of this compound, see below) in the presenceof a base such as triethylamine. The coupled product is then reduced byhydrogenation (Bioorg. Med. Chem. Lett., 1999, 9, 1625) to afford thedesired analog.

[2-(3-amino-2,6-dioxo-piperidin-1-yl)-ethyl]-phosphonic acid diethylester, 40.1, is obtained according to a procedure such as that reportedin J. Med. Chem., 2003, 46, 3793. Accordingly,benzyloxycarbonyl-protected glutaric acid is treated in a solvent suchas acetonitrile with triethylamine, 1-hydroxybenzotriazole, diethyl2-aminoethylphosphonate and 1,3-dicyclohexylcarbodiimide. After thereaction is complete, the solvent is removed and the residue is purifiedby chromatography to generate the cyclic product, which is subjected tohydrogen in the presence of palladium catalysis to afford the desiredintermediate.

Further manipulations can be performed on the phosphonate moiety priorto the final deprotection. These types of transformations are moreextensively described herein.

Example 41

The structures of Diprolene, 41A (German Patent DE 2905674), and theesters, 41.1-41.3, are shown below, in which the substituent R¹ is H,alkyl, alkenyl, aryl or aralkyl. The compounds, 41.1-41.3, incorporate aphosphonate moiety (R¹O)₂P(O) connected to the nucleus by means of avariable linking group, designated as “link” in the attached structures.

Example 42

A protection-deprotection sequence in which the steroid side-chain isprotected as a bis-methylenedioxy (BMD) moiety is shown above. Thepropionate ester groups of compound, 42.1, are hydrolyzed, for exampleby reaction with two molar equivalents of lithium hydroxide in aqueousdimethoxyethane solution at ambient temperature, to give the diol, 42.2.The product is then reacted with paraformaldehyde and an acid catalystsuch as hydrochloric acid, as described in “Protective Groups in OrganicSynthesis,” by T. W. Greene and P. G. M. Wuts, Wiley, Second Edition1990, p. 223, to yield the BMD derivative, 42.3. The phosphonate moietyis then introduced, using the procedures described below, to produce thephosphonate ester, 42.4. Prior to hydrolysis of the BMD protectinggroup, the 11-hydroxyl group is protected. The protecting group isselected so that it is stable to the conditions required for removal ofthe BMD group, and so that it is removable without affecting thesubsequently introduced 17,21-diester moiety.

For example, the 11-hydroxyl group is protected by conversion to the4-azidobutyrate ester, by reaction with 4-azidobutyryl chloride inpyridine. The 11-azidobutyrate group is then removed from the diester,42.7, by reaction with triphenylphosphine, as described in Bull. Soc.Chem. Jpn., 1986, 59, 1296. Alternatively, the 11-hydroxyl group isprotected by conversion to the 2-(tri-methylsilyl)ethyl carbonate, byreaction with 2-(trimethylsilyl)ethyl carbonyl chloride and pyridine.The 2-(trimethylsilyl) carbonate is removed from the diester, 42.7, byreaction with tetrabutylammonium fluoride in tetrahydrofuran at ambienttemperature, as described in Tet. Lett., 1981, 22, 969.

Alternatively, the 11-hydroxyl group is protected by conversion to thetrichloroacetyl ester, by reaction with trichloroacetyl chloride indimethylformamide-pyridine. The trichloroacetyl ester is removed byreaction with ethanolic ammonia at ambient temperature, as described inColl. Czech. Chem. Commun., 1962, 27, 2567.

The BMD moiety in the protected product, 42.5, is then hydrolyzed, forexample by treatment with 50% aqueous acetic acid, as described in“Protective Groups in Organic Synthesis,” by T. W. Greene and P. G. M.Wuts, Wiley, Second Edition 1990, p. 223, to afford the diol, 42.6. Thediol compound is then acylated, for example by reaction with propionicacid and dicyclohexyl carbodiimide in dimethylformamide at ambienttemperature, or by reaction with propionyl chloride and triethylamine indichloromethane, to produce the dipropionate, 42.7. Deprotection of the11-hydroxyl group, as described above, then affords the diester, 42.8.

Alternatively, the 20-ketone group is protected as the diethylamineadduct by reaction with titanium tetrakis(diethylamide), as described inProtective Groups in Organic Synthesis, by T. W. Greene and P. G. MWuts, Wiley, Second Edition 1990, p. 219.

Example 43

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino or iminoxy group and a variable carbon chain isillustrated above. In this procedure, the BMD-protected derivative,42.3, is reacted with an amine or hydroxylamine, 43.1, in which R² is analkyl, alkenyl, cycloalkyl or cycloalkenyl group, optionallyincorporating a heteroatom O, S or N, or a functional group such as anamide, ester, oxime, sulfoxide or sulfone etc, or an optionallysubstituted aryl, heteroaryl or aralkyl group, optionally incorporatinga heteroatom O, S or N, to afford the imine or iminoxy product, 43.2.The reaction is conducted between equimolar amounts of the reactants inan aprotic solvent such as pyridine or xylene, or in an alcoholicsolvent such as ethanol, optionally in the presence of an acid catalyst,to give the imine or oxime. The preparation of oximes of steroidal3-ketones is described in Anal. Bioch., 1978, 86, 133 and in J. Mass.Spectrom., 1995, 30, 497. The BMD-protected compound, 43.2, is thenconverted, as described above, into the diester, 43.3.

The preparation of hydroxylamine ethers incorporating a phosphonategroup is shown above. In this procedure, a phosphonate, 43.4, in whichLv is a leaving group such as bromo or trifluoromethylsulfonyloxy, isreacted with BOC-hydroxylamine, 43.5 (Aldrich), to produce the ether,43.6. The reaction is conducted between equimolar amounts of thereactants in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such as potassium hydroxideor dimethylaminopyridine, to give the product, 43.6. Deprotection, forexample by treatment with trifluoroacetic acid, then gives thehydroxylamine ether, 43.7.

Example 44

The preparation of phosphonates in which the phosphonate is attached bymeans of an iminoxy group is illustrated above. In this procedure, thesubstrate, 42.3, is reacted with a dialkyl phosphonomethylhydroxylamine, 44.1, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tetrahedron Lett., 1986,27, 1477) and BOC-hydroxylamine, to afford, after deprotection and sidechain acylation, the oxime ether, 44.2. The oxime forming reaction isperformed at ambient temperature in pyridine solution between equimolaramounts of the reactants.

Using the above procedures, but employing, in place of the oxime ether,44.1, different oxime ethers, 43.7, the corresponding products, 43.3 areobtained.

Example 45

The preparation of phosphonates incorporating an iminoxy group, by meansof the reaction between the substrate the substrate, 42.3, andO-2-(5-bromo-2-thienyl)ethoxyhydroxylamine, 45.1, prepared as describedabove from 2-(5-bromo-2-thienyl)ethyl bromide (J. Chem. Soc., PerkinTrans. Phys. Org. Chem., 1975, 821), is illustrated above. The resultantoxime ether is converted, by deprotection and side chain acylation, intothe compound, 45.2, which is then reacted, in the presence of apalladium catalyst, with a dialkyl phosphite, 45.3, to afford thephosphonate, 45.4. The preparation of arylphosphonates by means of acoupling reaction between aryl bromides and dialkyl phosphites isdescribed in J. Med. Chem., 1992, 35, 1371. The reaction is performed inan inert solvent such as toluene, in the presence of a base such astriethylamine and a catalytic amount oftetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo-substituted product, 45.2, is coupled, in apalladium-catalyzed Heck reaction, with a dialkyl propenyl phosphonate,45.5, (Acros) to give the unsaturated phosphonate, 45.6. The coupling ofaryl halides with olefins by means of the Heck reaction is described,for example, in “Advanced Organic Chemistry,” by F. A. Carey and R. J.Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem. Res., 1979, 12, 146.The aryl bromide and the olefin are coupled in a polar solvent such asdimethylformamide or dioxan, in the presence of a palladium(0) catalystsuch as tetrakis(triphenylphosphine)-palladium(0) or palladium(II)catalyst such as palladium(II) acetate, and optionally in the presenceof a base such as triethylamine or potassium carbonate.

Optionally, the styrenoid double bond present in the product, 45.6, isreduced, for example by reaction with diimide, to produce the saturatedanalog, 45.7. The reduction of olefinic bonds is described in“Comprehensive Organic Transformations,” by R. C. Larock, VCH, 1989, p.6ff. The transformation is effected by means of catalytic hydrogenation,for example using a palladium on carbon catalyst and hydrogen, or ahydrogen donor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of the bromothienylreagent, 45.1, different bromo-substituted aryl or heteroaryl alkoxyhydroxylamines, and/or different dialkyl alkenyl phosphonates, theproducts analogous to the compounds 45.4, 45.6 and 45.7 are obtained.

Example 46

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino group is illustrated above. In this procedure, thesubstrate, 42.3, which is reacted with a dialkyl 2-aminophenylphosphonate, 46.1 (Aurora), to give, after deprotection and side chainacylation, the imine product, 46.2. The reaction is conducted in ahydrocarbon solvent such as toluene or xylene, at reflux temperature, inthe presence of a basic catalyst such as sodium methoxide, or an acidcatalyst such as p-toluenesulfonic acid, under azeotropic conditions, togive the product, 46.2.

Using the above procedures, but employing, in place of the2-amino-phenyl phosphonate, 46.1, different amino-substituted aryl orheteroaryl phosphonates, products analogous to 46.2 are obtained.

Example 47

An alternative method for the preparation of phosphonates in which thephosphonate is attached by means of an oximino group is illustratedabove. In this procedure, the dienone, 42.3, is reacted withO-(carboxymethyl)hydroxyl-amine, 47.1 (Interchim), to yield, afterdeprotection and side chain acylation, the oxime, 47.2. The reaction ofsteroidal 1,4-dien-3-ones with hydroxylamine is described in J. SteroidBioch., 1976, 7, 795. The reaction is performed between equimolaramounts of the reactants in a polar organic solvent such as pyridine ormethanol, optionally in the presence of acetic acid or sodium acetate.The oxime, 47.2, is then reacted with a dialkyl 3-hydroxyphenylphosphonate, 47.3 (Epsilon), in a Mitsonobu reaction, to yield thesubstituted oxime, 47.4. The preparation of aromatic ethers andthioethers by means of the Mitsonobu reaction is described, for example,in “Comprehensive Organic Transformations,” by R. C. Larock, VCH, 1989,p. 448, and in “Advanced Organic Chemistry,” Part B, by F. A. Carey andR. J. Sundberg, Plenum, 2001, p. 153-4 and in Org. React., 1992, 42,335. The phenol and the hydroxy or mercapto component are reactedtogether in an aprotic solvent such as, for example, tetrahydrofuran, inthe presence of a dialkyl azodicarboxylate and a triarylphosphine, toafford the ether or thioether products. The procedure is also describedin Org. React., 1992, 42, 335-656. The product, 47.4, is thentransformed, by deprotection and acylation, into the diester, 47.5.

Using the above procedures, but employing, in place of the phosphonate,47.3, different dialkyl hydroxy-substituted aryl or heteroarylphosphonates, the products analogous to 47.5 are obtained.

Example 48

The preparation of the phosphonate esters in which the phosphonate groupis attached to the 1′ or 2′ position of the pyrazole ring, by means ofan aromatic or heteroaromatic group, a heteroatom and a variable carbonchain is illustrated above. In this procedure, Diprolene, 41A, isreduced to afford the 1,2-dihydro product, 48.1. The catalytichydrogenation reaction is effected by the use oftris(triphenylphosphine)rhodium (I) chloride, for example as describedin J. Med. Chem., 2001, 44, 602. The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in Australian PatentApplication 275950409, to afford the 2-formyl product, 48.2.

Optionally, the substrate, 41A, is protected, for example as describedin Example 42, above, prior to the formylation reaction, as described inJ. Am. Chem. Soc., 1964, 86, 1520. The 2-formyl product is then reactedwith an aryl or heteroaryl hydrazine, 48.3, in which the substituent Xis either a phosphonate group or a group which is subsequentlytransformed into a phosphonate-containing substituent. For example, X isdialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. Thereaction yields the isomeric 2′- and 1′-aryl pyrazoles, 48.4 and 48.5.The ring-forming reaction is performed between equimolar amounts of thereactants in an acidic solvent such as acetic acid, as described in J.Am. Chem. Soc., 1964, 86, 1520. The pyrazoles, 48.4 and 48.5 are thentransformed, for example by the procedures described in Examples 49-50,respectively into the phosphonates, 48.6 and 48.7.

Example 49

The preparation of phosphonates in which the phosphonate is attached bymeans of a phenyl group is illustrated above. In this sequence, theketoaldehyde, 48.2, is reacted, as described above, with2-bromophenylhydrazine, 49.1 (Fluka), to give the isomeric pyrazoleproducts, 49.2 and 49.3. The products are then reacted, as describedherein, with a dialkyl phosphite HP(O)(OR¹)₂ and a palladium catalyst,to afford respectively the phosphonates, 49.4 and 49.5. Using the aboveprocedures, but employing, in place of 2-bromophenyl hydrazine,different bromoaryl or bromoheteroaryl hydrazines, 48.3, the products,48.6 and 48.7 are obtained.

Example 50

The preparation of phosphonates in which the phosphonate is attached bymeans of an aromatic or heteroaromatic group and a saturated orunsaturated alkyl chain is illustrated above. In this procedure, thebromophenyl-substituted pyrazole, 49.2, is coupled in a Heck reaction,as described above, with, for example a dialkyl butenyl phosphonate,50.1, (Org. Lett., 2001, 3, 217) to give the unsaturated phosphonateproduct, 50.2. Optionally, the product is reduced, as described above,to give the saturated analog, 50.3. Application of the above proceduresto the isomeric bromophenyl pyrazole, 49.3, affords the productsisomeric with, 50.2 and 50.3. Using the above procedures, but employing,in place of the phosphonate, 50.1, different dialkyl alkenylphosphonates, and/or different bromoaryl or heteroaryl pyrazoles, 48.4or 48.5, the products analogous to 50.2 and 50.3 are obtained.

Example 51

The preparation of phosphonates, 51.5 and 51.6, in which the phosphonateis attached by means of an aryl or heteroaryl group and an alkoxy chainis illustrated above. In this procedure, 4-Aminothiophenol, 51.1, isreacted in dimethylformamide solution at ambient temperature with adialkyl trifluoro-methanesulfonyloxymethyl phosphonate, 51.2(Tetrahedron Lett., 1986, 27, 1477), and potassium carbonate to give thethioether, 51.3. The product is then converted into the correspondinghydrazine, 51.4, by means of a diazotization reaction in aqueousethanolic hydrochloric acid, followed by reduction of the diazoniumchloride with tin(II) chloride, as described in J. Med. Chem., 2001, 44,4031. The hydrazine is then reacted, as described above, with theketoaldehyde, 48.2, to form the isomeric pyrazoles, 51.5 and 51.6.

Using the above procedures, but employing, in place of the triflate,51.2, different dialkylphosphono alkyl bromides or triflates, and/ordifferent aromatic or heteroaromatic mercapto or hydroxyamines, theproducts analogous to 51.5 and 51.6 are obtained.

Example 52

The preparation of phosphonates in which the phosphonate is attached bymeans of a pyridyl group a heteroatom and a variable carbon chain isillustrated above. In this procedure, 3-amino-5-hydroxypyridine, 52.1,is converted, by reaction with acetic anhydride, into the diacetylanalog, 52.2. The product is then transformed by diazotization andreduction, as described above, into the hydrazine, 52.3. The hydrazine,52.3, is then reacted with the ketoaldehyde, 48.2, to give the isomericpyrazoles, 52.4 and 52.5. The 2′-pyridyl product, 52.4, is reacted in aMitsonobu reaction, as described above, with a dialkyl hydroxyethylphosphonate, 52.6 (Zh. Obschei. Khim., 1973, 43, 2364), to afford theether, 52.7. Application of this procedure to the isomeric phenol, 52.5,affords the product isomeric to compound, 52.7.

Alternatively, the isomeric phenol, 52.5, is reacted, indimethyl-formamide solution at about 800, with one molar equivalent of adialkyl bromopropynyl phosphonate, 52.8 (Bioorg. Med. Chem. Lett., 1994,4, 273), and cesium carbonate, to prepare the phosphonate, 52.9.Application of this procedure to the isomeric phenol, 52.4, affords theproduct isomeric with compound, 52.4. Using the above procedures, butemploying, in place of the carbinol, 52.6, or the bromide, 52.8,different thiols, alcohols or bromides, and/or different phenols, 48.4or 48.5, in which X is OH, the corresponding products analogous to 52.7and 52.9 are obtained.

Example 53

The preparation of the phosphonate esters in which the phosphonate groupis attached by means of a variable carbon linkage is illustrated above.In this procedure, the ketoaldehyde, 48.2, is reacted with hydrazine, toafford the pyrazole derivative, 53.1. The reaction of steroidal2-formyl-3-ketones with hydrazine is described in J. Am. Chem. Soc,1964, 86, 1520. The reaction is performed in acetic acid at ambienttemperature. The resulting pyrazole is then reacted with a dialkylbromomethyl phosphonate, 53.2, in which R² is as defined above, toproduce the isomeric 2′ and 1′ alkylation products, 53.3 and 53.4,respectively. The alkylation of substituted pyrazoles is described, forexample, in “Heterocyclic Chemistry,” by T. L. Gilchrist, Longman, 1992,p. 309.

Example 54

Pyrazole, 53.1, is reacted, in dimethylformamide solution at ca. 90°,with a dialkyl bromopropyl phosphonate, 54.1 (Aldrich), and a base suchas dimethylaminopyridine or lithium hexamethyldisilazide, to yield theisomeric alkylation products, 54.2 and 54.3.

As shown in Scheme 54A, the pyrazole, 53.1, is reacted indimethyl-formamide solution at ambient temperature with one molarequivalent of 1,4-dibromobut-2-yne, 54.4 (Narchem), and potassiumcarbonate, to afford the alkylation products, 54.5 and 54.6. Theproducts are then heated at 120° with a trialkyl phosphite in an Arbuzovreaction, to yield the phosphonates, 54.7 and 54.8. The Arbuzov reactionis described in Handb. Organophosphorus Chem., 1992, 115-72. Using theabove procedures, but employing, in place of the dibromide, 54.4,different alkyl, alkenyl or alkynyl dibromides, the products analogousto 54.7 and 54.8 are obtained.

Example 55

The structures of Aclometasone dipropionate, 55/A (J. Med. Chem., 1980,23, 430; U.S. Pat. No. 4,124,707), and the esters, 55A-55C, are shownbelow, in which the substituent R¹ is H, alkyl, alkenyl, aryl oraralkyl. The compounds, 55A-55C, incorporate a phosphonate moiety(R¹O)₂P(O) connected to the nucleus by means of a variable linkinggroup, designated as “link” in the attached structures.

The steroid side-chain is protected as a bis-methylenedioxy (BMD)moiety, as illustrated in Scheme 55A. In this sequence, the propionateesters are hydrolyzed, for example by reaction with two molarequivalents of lithium hydroxide in aqueous dimethoxyethane solution atambient temperature, to give the diol, 55.1. The product is then reactedwith paraformaldehyde and an acid catalyst such as hydrochloric acid, asdescribed in “Protective Groups in Organic Synthesis,” by T. W. Greeneand P. G. M. Wuts, Wiley, Second Edition 1990, p. 223, to yield the BMDderivative, 55.2. The phosphonate moiety is then introduced, using theprocedures described below, to produce the phosphonate ester, 55.3.Prior to hydrolysis of the BMD protecting group, the 11-hydroxyl groupis protected. The protecting group is selected so that it is stable tothe conditions required for removal of the BMD group, and so that it isremovable without affecting the subsequently introduced 17,21-diestermoiety. For example, the 11-hydroxyl group is protected by conversion tothe 4-azido-butyrate ester, by reaction with 4-azidobutyryl chloride inpyridine. The 11-azidobutyrate group is then removed from the diester,55.6, by reaction with triphenylphosphine, as described in Bull. Soc.Chem. Jpn., 1986, 59, 1296. Alternatively, the 11-hydroxyl group isprotected by conversion to the 2-(tri-methylsilyl)ethyl carbonate, byreaction with 2-(trimethylsilyl)ethyl carbonyl chloride and pyridine.The 2-(trimethylsilyl) carbonate is removed from the diester, 55.6, byreaction with tetrabutylammonium fluoride in tetrahydrofuran at ambienttemperature, as described in Tet. Lett., 1981, 22, 969.

Alternatively, the 11-hydroxyl group is protected by conversion to thetrichloroacetyl ester, by reaction with trichloroacetyl chloride indimethyl-formamidepyridine. The trichloroacetyl ester is removed byreaction with ethanolic ammonia at ambient temperature, as described inColl. Czech. Chem. Commun., 1962, 27, 2567. The BMD moiety in theprotected product, 55.4, is then hydrolyzed, for example by treatmentwith 50% aqueous acetic acid, as described in “Protective Groups inOrganic Synthesis,” by T. W. Greene and P. G. M. Wuts, Wiley, SecondEdition 1990, p. 223, to afford the diol, 55.5. The diol, 55.5, isacylated, for example by reaction with propionic acid and dicyclohexylcarbodiimide in dimethylformamide at ambient temperature, or by reactionwith propionyl chloride and triethylamine in dichloromethane, to producethe dipropionate, 55.6. Deprotection of the 11-hydroxyl group, asdescribed above, then affords the diester, 55.7.

Alternatively, the 20-ketone group is protected as the diethylamineadduct by reaction with titanium tetrakis(diethylamide), as described in“Protective Groups in Organic Synthesis,” by T. W. Greene and P. G. MWuts, Wiley, Second Edition 1990, p. 219.

Example 56

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino or iminoxy group and a variable carbon chain isillustrated above. In this procedure, the BMD-protected derivative,55.2, is reacted with an amine or hydroxylamine, 56.1, in which R² is analkyl, alkenyl, cycloalkyl or cycloalkenyl group, optionallyincorporating a heteroatom O, S or N, or a functional group such as anamide, ester, oxime, sulfoxide or sulfone etc, or an optionallysubstituted aryl, heteroaryl or aralkyl group, optionally incorporatinga heteroatom O, S or N, to afford the imine or iminoxy product, 56.2.The reaction is conducted between equimolar amounts of the reactants inan aprotic solvent such as pyridine or xylene, or in an alcoholicsolvent such as ethanol, optionally in the presence of an acid catalystto give the imine or oxime. The preparation of oximes of steroidal3-ketones is described in Anal. Bioch., 1978, 86, 133 and in J. Mass.Spectrom., 1995, 30, 497. The BMD-protected side-chain compound, 56.2,is then converted into the diester, 56.3.

Example 56A

Also illustrated is the preparation of hydroxylamine ethersincorporating a phosphonate group. A phosphonate, 56.4, in which Lv is aleaving group such as bromo or trifluoromethylsulfonyloxy, is reactedwith BOC-hydroxylamine, 56.5 (Aldrich), to produce the ether, 56.6. Thereaction is conducted between equimolar amounts of the reactants in apolar solvent such as dimethyl-formamide or tetrahydrofuran, in thepresence of a base such as potassium hydroxide or dimethylaminopyridine,to give the product, 56.6. Deprotection, for example by treatment withtrifluoroacetic acid, then gives the hydroxylamine ether, 56.7.

Example 56B

The preparation of phosphonates in which the phosphonate is attached bymeans of an iminoxy group is illustrated above. In this procedure, thesubstrate, 55.2, is reacted with a dialkyl phosphonomethylhydroxylamine, 56.1, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tetrahedron Lett., 1986,27, 1477) and BOC-hydroxylamine, to afford, after deprotection and sidechain acylation, the oxime ether, 56.2. The oxime forming reaction isperformed at ambient temperature in pyridine solution between equimolaramounts of the reactants.

Using the above procedures, but employing, in place of the oxime ether,56.1, different oxime ethers, 56.7, the corresponding products, 56.2 areobtained.

Example 57

The preparation of phosphonates incorporating an iminoxy group, by meansof the reaction between the substrate, 55.2, andO-2-(3-bromophenyl)-ethylhydroxylamine, 57.1, prepared as describedabove from compound, 55.1, and 2-(3-bromophenyl)ethyl bromide,respectively. The resultant oxime ether is converted, by deprotectionand side chain acylation, into the compound, 57.2, which is thenreacted, in the presence of a palladium catalyst, with a dialkylphosphite, 57.3, to afford the phosphonate, 57.4. The preparation ofarylphosphonates by means of a coupling reaction between aryl bromidesand dialkyl phosphites is described in J. Med. Chem., 1992, 35, 1371.The reaction is performed in an inert solvent such as toluene, in thepresence of a base such as triethylamine and a catalytic amount oftetrakis(triphenylphosphine)-palladium(0).

Alternatively, the bromo-substituted product, 57.2, is coupled, in apalladium-catalyzed Heck reaction, with a dialkyl vinyl phosphonate,57.5 (Aldrich), to give the unsaturated phosphonate, 57.6. The couplingof aryl halides with olefins by means of the Heck reaction is described,for example, in “Advanced Organic Chemistry,” by F. A. Carey and R. J.Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem. Res., 1979, 12, 146.The aryl bromide and the olefin are coupled in a polar solvent such asdimethylformiamide or dioxan, in the presence of a palladium(0) catalystsuch as tetrakis(triphenylphosphine)-palladium(0) or a palladium(II)catalyst such as palladium(II) acetate, and optionally in the presenceof a base such as triethylamine or potassium carbonate. Optionally, thestyrenoid double bond present in the product, 57.6, is reduced, forexample by reaction with diimide, to produce the saturated analog, 57.7.The reduction of olefinic bonds is described in “Comprehensive OrganicTransformations,” by R. C. Larock, VCH, 1989, p. 6ff. The transformationis effected by means of catalytic hydrogenation, for example using apalladium on carbon catalyst and hydrogen or a hydrogen donor, or by theuse of diimide or diborane.

Using the above procedures, but employing, in place of the bromophenylreagent, 57.1, different bromo-substituted aryl or heteroaryl alkoxyhydroxylamines, and/or different dialkyl alkenyl phosphonates, theproducts analogous to the compounds, 57.4, 57.6 and 57.7 are obtained.

Example 58

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino group is illustrated above. In this procedure, thesubstrate, 55.2, is reacted with a dialkyl 3-aminophenyl phosphonate,58.1 (J. Med. Chem., 1984, 27, 654), to give, after deprotection andside chain acylation, the imine product, 58.2. The reaction is conductedin a hydrocarbon solvent such as toluene or xylene, at refluxtemperature, in the presence of a basic catalyst such as sodiummethoxide, or an acid catalyst such as p-toluenesulfonic acid, underazeotropic conditions, to give the product, 58.2.

Using the above procedures, but employing, in place of the 3-aminophenylphosphonate, 58.1, different amino-substituted aryl or heteroarylphosphonates, products analogous to 58.2 are obtained.

An alternative method for the preparation of phosphonates, 58.3, wherethe phosphonate is attached by means of an oximino group starts with thedienone, 55.2, is illustrated above. The dienone is reacted withhydroxylamine to yield, after deprotection and side chain acylation, theoxime, 58.3. The reaction of steroidal 1,4-dien-3-ones withhydroxylamine is described in J. Steroid Bioch., 1976, 7, 795; thereaction is performed between equimolar amounts of the reactants in apolar organic solvent such as pyridine or methanol, optionally in thepresence of acetic acid or sodium acetate. The oxime is then reactedwith a dialkyl 3-hydroxyphenyl phosphonate, 58.4 (Epsilon), in aMitsonobu reaction, to yield the substituted oxime, 58.5. Thepreparation of aromatic ethers and thioethers by means of the Mitsonobureaction is described, for example, in “Comprehensive OrganicTransformations,” by R. C. Larock, VCH, 1989, p. 448, and in “AdvancedOrganic Chemistry,” Part B, by F. A. Carey and R. J. Sundberg, Plenum,2001, p. 153-4 and in Org. React., 1992, 42, 335. The phenol and thehydroxy or mercapto component are reacted together in an aprotic solventsuch as, for example, tetrahydrofuran, in the presence of a dialkylazodicarboxylate and a triarylphosphine, to afford the ether orthioether products. The procedure is also described in Org. React.,1992, 42, 335-656.

Using the above procedures, but employing, in place of the phosphonate,58.4, different dialkyl hydroxy-substituted aryl or heteroarylphosphonates, the products analogous to 58.5 are obtained.

Example 59

The preparation of the phosphonate esters in which the phosphonate groupis attached to the 1′ or 2′ position of the pyrazole ring, by means ofan aromatic or heteroaromatic group, a heteroatom and a variable carbonchain is shown above. In this procedure, Aclometasone dipropionate, 59A,is reduced to afford the 1,2-dihydro product, 59.1. The catalytichydrogenation reaction is effected by the use oftris(triphenylphosphine)rhodium (I) chloride, for example as describedin J. Med. Chem., 2001, 44, 602. The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in Australian PatentApplication 275950409, to afford the 2-formyl product, 59.2. Optionally,the substrate, 59A, is protected, for example, as described above inExample 55, prior to the formylation reaction, as described in J. Am.Chem. Soc., 1964, 86, 1520. The 2-formyl product is then reacted with anaryl or heteroaryl hydrazine, 59.3, in which the substituent X is eithera phosphonate group or a group which is subsequently transformed into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxyl and the like. The reaction yields theisomeric 2′- and 1′-aryl pyrazoles, 59.4 and 59.5. The ring-formingreaction is performed between equimolar amounts of the reactants in anacidic solvent such as acetic acid, as described in J. Am. Chem. Soc.,1964, 86, 1520. The pyrazoles, 59.4 and 59.5, are then transformed, forexample by the procedures described in Examples 60-65, respectively intothe phosphonates, 59.6 and 59.7.

Example 60

The preparation of phosphonates in which the phosphonate is attached bymeans of a phenyl group is illustrated above. In this sequence, theketoaldehyde, 59.2, is reacted, as described above, with3-bromophenylhydrazine, 60.1 (Fluka), to give the isomeric pyrazoleproducts, 60.2 and 60.3. The products are then reacted, as describedabove, with a dialkyl phosphite HP(O)(OR¹)₂ and a palladium catalyst, toafford respectively the phosphonates, 60.4 and 60.5. Using the aboveprocedures, but employing, in place of 3-bromophenyl hydrazine,different bromoaryl or bromoheteroaryl hydrazines, 59.3, thecorresponding products, 59.6 and 59.7 are obtained.

Example 60A

The preparation of phosphonates in which the phosphonate is attached bymeans of an aromatic or heteroaromatic group and a saturated orunsaturated alkyl chain is illustrated above. In this procedure, thebromophenyl-substituted pyrazole, 60.2, is coupled in a Heck reaction,as described above, with, for example a dialkyl vinyl phosphonate, 60.6(Aldrich), to give the unsaturated phosphonate product, 60.7.Optionally, the product is reduced, as described above, to give thesaturated analog, 60.8. Application of the above procedures to theisomeric bromophenyl pyrazole, 60.3, affords the products isomeric with,60.7 and 60.8.

Using the above procedures, but employing, in place of the phosphonate,60.6, different dialkyl alkenyl phosphonates, and/or different bromoarylor heteroaryl pyrazoles, 59.4 or 59.5 (X═Br), the products analogous to60.7 and 60.8 are obtained.

Example 61

The preparation of phosphonates in which the phosphonate is attached bymeans of an aryl or heteroaryl group and an alkoxy chain is illustratedabove. In this procedure, 4-aminophenol, 61.1, is reacted indimethylformamide solution at ambient temperature with a dialkyltrifluoromethanesulfonyloxymethyl phosphonate, 61.2 (Tetrahedron Lett.,1986, 27, 1477), and potassium carbonate to give the ether, 61.3. Theproduct is then converted into the corresponding hydrazine, 61.4, bymeans of a diazotization reaction in aqueous ethanolic hydrochloricacid, followed by reduction of the diazonium chloride with tin(II)chloride, as described in J. Med. Chem., 2001, 44, 4031. The hydrazineis then reacted, as described above, with the ketoaldehyde, 59.2, toform the isomeric pyrazoles, 61.5 and 61.6.

Using the above procedures, but employing, in place of the triflate,61.2, different dialkylphosphono alkyl bromides or triflates, and/ordifferent aromatic or heteroaromatic hydroxyamines, the productsanalogous to 61.5 and 61.6 are obtained.

Example 62

The preparation of phosphonates in which the phosphonate is attached bymeans of a pyridyl group, a heteroatom, and a variable carbon chain isshown herein. In this procedure, 3-amino-5-hydroxypyridine, 62.1, isconverted, by reaction with acetic anhydride, into the diacetyl analog,62.2. The product is then transformed by diazotization and reduction, asdescribed above, into the hydrazine, 62.3.

The hydrazine, 62.3, is then reacted with the ketoaldehyde, 59.2, togive the isomeric pyrazoles, 62.4 and 62.5. The 2′-pyridyl product,62.4, is reacted in a Mitsonobu reaction, as described above, with adialkyl mercaptoethyl phosphonate, 62.6 (Zh. Obschei. Khim., 1973, 43,2364), to afford the thioether, 62.7. Application of this procedure tothe isomeric phenol, 62.5, affords the product isomeric to, 62.7.

Alternatively, the isomeric phenol, 62.5, is reacted, indimethyl-formamide solution at ca. 80°, with one molar equivalent of adialkyl bromo-butenyl phosphonate, 62.8 (J. Med. Chem., 1992, 35, 1371),and cesium carbonate, to prepare the phosphonate, 62.9. Application ofthis procedure to the isomeric phenol, 62.4, affords the productisomeric with, 62.9.

Using the above procedures, but employing, in place of the thiol, 62.6,or the bromide, 62.8, different thiols, alcohols or bromides, and/ordifferent phenols, 59.4 or 59.5, in which X is OH, the correspondingproducts analogous to 62.7 and 62.9 are obtained.

Example 63

The preparation of the phosphonate esters in which the phosphonate groupis attached by means of a variable carbon linkage is illustrated above.In this procedure, the ketoaldehyde, 59.2, is reacted with hydrazine, toafford the pyrazole derivative, 63.1. The reaction of steroidal2-formyl-3-ketones with hydrazine is described in J. Am. Chem. Soc,1964, 86, 1520. The reaction is performed in acetic acid at ambienttemperature. The resulting pyrazole is then reacted with a dialkylbromomethyl phosphonate, 63.2, in which R² is as defined above, toproduce the isomeric 2′ and 1′ alkylation products, 63.3 and 63.4,respectively. The alkylation of substituted pyrazoles is described, forexample, in “Heterocyclic Chemistry,” by T. L. Gilchrist, Longman, 1992,p. 309.

Example 64

The pyrazole, 63.1, is reacted, in dimethylformamide solution at ca.90°, with a dialkyl bromopropyl phosphonate, 64.1 (Aldrich), and a basesuch as dimethylaminopyridine or lithium hexamethyldisilazide, to yieldthe isomeric alkylation products, 64.2 and 64.3.

Example 65

Pyrazole, 63.1, is reacted, as described above, with a dialkyl4-bromomethyl benzyl phosphonate, 65.1 (Tet., 1998, 54, 9341), to givethe products, 65.2 and 65.3.

Example 66

The structures of Hydrocortisone, 66A (U.S. Pat. No. 2,602,769) and thephosphonate esters are shown below, in which the substituent R¹ is H,alkyl, alkenyl, aryl or aralkyl. These compounds incorporate aphosphonate moiety (R¹O)₂P(O) connected to the nucleus by means of avariable linking group, designated as “link” in the attached structures.A general protection-deprotection sequence in which the steroidside-chain is protected as a bis-methylenedioxy (BMD) moiety is shownbelow.

Hydrocortisone, 66A, is reacted with paraformaldehyde and an acidcatalyst such as hydrochloric acid, as described “Protective Groups inOrganic Synthesis,” by T. W. Greene and P. G. M. Wuts, Wiley, SecondEdition 1990, p. 223, to yield the BMD derivative, 66.1. The phosphonatemoiety is then introduced, using the procedures described below, toproduce the phosphonate ester, 66.2. The BMD moiety is then hydrolyzed,for example by treatment with 50% aqueous acetic acid, as described in“Protective Groups in Organic Synthesis,” by T. W. Greene and P. G. M.Wuts, Wiley, Second Edition 1990, p. 223, to afford the triol, 66.3

Example 66A

The BMD-protected derivative, 66.1, is reacted with an amine orhydroxylamine, 66.4, in which R² is an alkyl, alkenyl, cycloalkyl orcycloalkenyl group, optionally incorporating a heteroatom O, S or N, ora functional group such as an amide, ester, oxime, sulfoxide or sulfoneetc, or an optionally substituted aryl, heteroaryl or aralkyl group,optionally incorporating a heteroatom O, S or N, and X is either aphosphonate group or a group which is subsequently converted into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxy and the like. The reaction is conductedbetween equimolar amounts of the reactants in an aprotic solvent such aspyridine or xylene, or in an alcoholic solvent such as ethanol,optionally in the presence of an acid catalyst, to give the imine oroxime, 66.5. The preparation of oximes of steroidal 3-ketones isdescribed in Anal. Bioch., 1978, 86, 133 and in J. Mass. Spectrom.,1995, 30, 497. In cases in which X is not dialkylphosphono, thesubstituent X is converted, using the methods described below; into aphosphonate-containing substituent; the BMD-protected side-chain is thenremoved to afford the triol, 66.6.

Example 66B

The preparation of hydroxylamine ethers incorporating a phosphonategroup is illustrated above. In this procedure, a phosphonate, 66.7, inwhich Lv is a leaving group such as bromo or trifluoromethylsulfonyloxy,is reacted with BOC-hydroxylamine, 66.8 (Aldrich), to produce the ether,66.9. The reaction is conducted between equimolar amounts of thereactants in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such as potassium hydroxideor dimethylaminopyridine. Deprotection, for example by treatment withtrifluoroacetic acid, then gives the hydroxylamine ether, 66.10.

Example 67

The substrate, 66.1, is reacted with a dialkyl phosphonomethylhydroxyl-amine, 67.1, prepared as described above from a dialkyltrifluoromethylsulfonyl-oxymethyl phosphonate (Tetrahedron Lett., 1986,27, 1477) and BOC-hydroxylamine, to afford the oxime, 67.2, which isdeprotected to afford the triol, 67.3. The oxime forming reaction isperformed at ambient temperature in ethanol-acetic acid solution betweenequimolar amounts of the reactants. Using the above procedures, butemploying, in place of the hydroxylamine ether, 67.1, different oximeethers, 66.10, the corresponding products, 66.6 are obtained.

Example 68

The preparation of compounds in which the phosphonate group is attachedby means of a phenyl ethoxy group is illustrated above. In thisprocedure, the enone, 66.1, is reacted, as described above, withO-(3-bromo-phenyl)ethyl hydroxylamine, 68.1, prepared as described abovefrom 2-(3-bromophenyl)ethyl bromide (French Patent FR 1,481,052), togive, after deprotection of the side-chain, the oxime, 68.2. The productis then reacted, in the presence of a palladium catalyst, with a dialkylphosphite, 68.3, to afford the phosphonate, 68.4. The preparation ofarylphosphonates by means of a coupling reaction between aryl bromidesand dialkyl phosphites is described in J. Med. Chem., 1992, 35, 1371.The reaction is performed in an inert solvent such as toluene, in thepresence of a base, such as triethylamine, and a catalytic amount oftetrakis(triphenylphosphine)palladium(0).

Example 68A

Alternatively, the bromo compound, 68.2, is coupled with a dialkylvinylphosphonate, 68.5 (Aldrich), to afford the phosphonate, 68.6. Thecoupling of aryl halides with olefins by means of the Heck reaction isdescribed, for example, in “Advanced Organic Chemistry,” by F. A. Careyand R. J. Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem. Res., 1979,12, 146. The aryl bromide and the olefin are coupled in a polar solventsuch as dimethylformamide or dioxan, in the presence of a palladium(0)catalyst such as tetrakis(triphenylphosphine)palladium(0) orpalladium(II) catalyst such as palladium(II) acetate, and optionally inthe presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product 68.6 isreduced, for example by reaction with diimide, to produce the saturatedanalog, 68.7. The reduction of olefinic bonds is described in“Comprehensive Organic Transformations,” by R. C. Larock, VCH, 1989, p.6ff. The transformation is effected by means of catalytic hydrogenation,for example using a palladium on carbon catalyst and hydrogen or ahydrogen donor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of the bromophenylethoxy reagent, 68.1, different bromo-substituted aryl or heteroarylalkoxy hydroxylamines, and/or different dialkyl alkenyl phosphonates,the products analogous to the compounds, 68.4, 68.6 and 68.7 areobtained.

Example 69

The enone, 66.1, is reacted with O-(2-aminoethyl)hydroxylamine, 69.1,(Pol. J. Chem., 1981, 55, 1163) to yield the oxime, 69.2. The reactionof steroidal 1,4-dien-3-ones with substituted hydroxylamines isdescribed in J. Steroid Bioch., 1976, 7, 795. The reaction is performedbetween equimolar amounts of the reactants in a polar organic solventsuch as pyridine or methanol, optionally in the presence of acetic acidor sodium acetate. The oxime is then coupled with a dialkyl4-carboxyphenyl phosphonate, 69.3 (Epsilon), to yield the amide oxime,69.4. The preparation of amides from carboxylic acids and derivatives isdescribed, for example, in Organic Functional Group Preparations, by S.R. Sandler and W. Karo, Academic Press, 1968, p. 274, and ComprehensiveOrganic Transformations, by R. C. Larock, VCH, 1989, p. 972ff. Thecarboxylic acid is reacted with the amine in the presence of anactivating agent, such as, for example, dicyclohexylcarbodiimide ordiisopropylcarbodiimide, optionally in the presence of, for example,hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxypyridone, in anon-protic solvent such as, for example, pyridine, DMF ordichloromethane, to afford the amide.

Alternatively, the carboxylic acid (e.g., dialkyl 4-carboxyphenylphosphonate, 69.3) is first converted into an activated derivative suchas the acid chloride, anhydride, mixed anhydride, imidazolide and thelike, and then reacted with the amine, in the presence of an organicbase such as, for example, pyridine, to afford the amide. The conversionof a carboxylic acid into the corresponding acid chloride is effected bytreatment of the carboxylic acid with a reagent such as, for example,thionyl chloride or oxalyl chloride in an inert organic solvent such asdichloromethane, optionally in the presence of a catalytic amount ofdimethylformamide. The amide product, 69.4, is then converted, asdescribed herein, into the triol, 69.5.

Using the above procedures, but employing, in place of thehydroxylamine, 69.1, different amino-substituted hydroxylamines, and/ordifferent carboxy-substituted phosphonates, the products analogous to69.5 are obtained.

Example 70

The preparation of the phosphonate esters in which the phosphonate groupis attached to the 1′ or 2′ position of the pyrazole ring, by means of avariable carbon chain is illustrated above. In this procedure, theBMD-protected enone, 66.1, is reacted with ethyl formate and a base suchas sodium hydride, in an inert solvent such as toluene ordimethylformamide, as described in J. Am. Chem. Soc., 1964, 86, 1520, toafford the 2-formyl product, 70.1. This compound is then reacted with analkyl, aralkyl, aryl or heteroaryl hydrazine, 70.2, wherein R² is alkyl,aralkyl, aryl, or heteroaryl, and in which the substituent X is either aphosphonate group or a group which is subsequently transformed into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxyl and the like. The reaction yields theisomeric 2′- and 1′-aryl pyrazoles, 70.3 and 70.4. The pyrazole-formingreaction is performed between equimolar amounts of the reactants in anacidic solvent such as acetic acid, as described in J. Am. Chem. Soc.,1964, 86, 1520. The pyrazoles, 70.3 and 70.4, are then transformed, forexample, using procedures described herein, via the BMD-protectedintermediates, 70.5 and 70.6, into the phosphonates, 70.7 and 70.8.

Example 71

The preparation of phosphonates in which the phosphonate moiety isattached by means of a phenyl ring and an amide linkage is illustratedabove. In this procedure, the ketoaldehyde, 70.1, is reacted, with3-carbomethoxyphenyl-hydrazine, 71.1 (Apin), to give the pyrazoles, 71.2and 71.3. The 2′-substituted isomer, 71.2, is then reacted with onemolar equivalent of lithium hydroxide in aqueous dimethoxyethane, toproduce the carboxylic acid, 71.4. The acid is then coupled, asdescribed above, with a dialkyl aminomethyl phosphonate, 71.5,(Interchim) to give the amide, 71.6, deprotection then affords thetriol, 71.7. Alternatively, the 1′-substituted pyrazole, 71.3, ishydrolyzed, as described above, to the carboxylic acid, 71.8. Theproduct is then coupled with a dialkyl 3-aminophenyl phosphonate, 71.9(J. Med. Chem., 1984, 27, 654), to yield after deprotection the triolamide, 71.10.

Using the above procedures, but employing, in place of thecarbomethoxyphenyl hydrazine, 71.1, different carbomethoxy-substitutedaralkyl, aryl or heteroaryl alkoxy hydrazines, and/or different dialkylamino-substituted phosphonates, the products analogous to the compounds,71.7 and 71.10 are obtained.

Example 72

The preparation of the phosphonate esters in which the phosphonate groupis attached by means of a variable carbon linkage is illustrated above.In this procedure, the ketoaldehyde, 70.1, is reacted, as describedabove, with 4-bromophenyl hydrazine, 72.1 (J. Organomet. Chem., 1999,62, 581), to produce the pyrazoles, 72.2 and 73.3. The 1′-substitutedisomer, 72.2, is coupled, as described herein, in the presence of apalladium catalyst, with a dialkyl butenyl phosphonate, 72.4 (Org.Lett., 2001, 3, 217), to give the phosphonate, 72.5. The product is thendeprotected to afford the triol, 72.6. Optionally, the styrenoid doublebond present in the product, 72.6, is reduced, as described above, toproduce the saturated analog, 72.7.

Alternatively, the 2′-substituted pyrazole, 72.3, is coupled, in thepresence of a palladium catalyst, with a dialkyl phosphite to preparethe phosphonate, 72.8, which is deprotected to give the triol, 72.9. Thepreparation of arylphosphonates by means of a coupling reaction betweenaryl bromides and dialkyl phosphites is described in J. Med. Chem.,1992, 35, 1371. This reaction is performed in an inert solvent such astoluene, in the presence of a base such as triethylamine andtetrakis(triphenylphosphine)-palladium(0).

Using the above procedures, but employing, in place of the bromophenylhydrazine, 72.1, different bromo-substituted aralkyl, aryl or heteroarylalkoxy hydrazines, and/or different dialkyl alkenyl phosphonates, theproducts analogous to the compounds, 72.6, 72.7 and 72.9 are obtained.

Example 73

The preparation of the phosphonate esters in which the phosphonate groupis attached by means of a variable carbon linkage is illustrated above.In this procedure, the ketoaldehyde, 70.1, is reacted with hydrazine, toafford the pyrazole derivative, 73.1. The reaction of steroidal2-formyl-3-ketones with hydrazine is described in J. Am. Chem. Soc,1964, 86, 1520. The reaction is performed in ethanol at refluxtemperature. The pyrazole product is then reacted with a bromomethylcompound, 73.2, in which R² and X are as defined above, to yield thealkylation products, 73.3 and 73.4. The alkylation of substitutedpyrazoles is described, for example, in “Heterocyclic Chemistry,” by T.L. Gilchrist, Longman, 1992, p. 309.

The reaction is performed between equimolar amounts of the substrates ina polar solvent such as dimethylformamide or tetrahydrofuran, in thepresence of a base such as dimethylaminopyridine, lithiumhexamethyldisilazide and the like. The products, 73.3 and 73.4, areconverted into the phosphonates, 73.5 and 73.6, except in cases where Xis dialkylphosphono, using the procedures described herein. Deprotectionaffords the triols, 73.7 and 73.8.

Example 74

The pyrazole, 73.1, is reacted, as described above, with one molarequivalent of a dialkyl 4-(bromomethyl)phenyl phosphonate, 74.1 (WO2003/042150), to give the alkylated pyrazoles, 74.2 and 74.3.Deprotection then yields the triols, 74.4 and 74.5.

Example 75

The pyrazole, 73.1, is reacted, as described above, with2,5-bis(bromo-methyl)thiophene, 75.1 (Tet., 1999, 55, 4709), to give thepyrazoles, 75.2 and 75.3. The products are subjected to an Arbuzovreaction, in which the bromomethyl substituent is converted into thedialkyl phosphonomethyl substituent, by reaction with a trialkylphosphite at 120°, to prepare, after deprotection of the side chain, thephosphonates, 75.4 and 75.5. The Arbuzov reaction is described in Handb.Organophosphorus Chem., 1992, 115-72. In the procedure, the substrate isheated at from 60° to about 160° with a five to fifty-fold molar excessof the trialkyl phosphite.

Using the above procedures, but employing, in place of the dibromide,75.1, different dibromides, the products analogous to 75.4 and 75.5 areobtained.

Example 76

Dexamethasone, 76A, (U.S. Pat. No. 3,007,923) analogs where thesubstituent R¹ is H, alkyl, alkenyl, aryl or aralkyl are prepared by theprocedures below. The compounds 76.1-76.3 incorporate a phosphonatemoiety (R¹O)₂P(O) connected to the nucleus by means of a variablelinking group, designated as “link” in the attached structures.

Dexamethasone, 76A, is reacted with paraformaldehyde and an acidcatalyst such as hydrochloric acid, as described in “Protective Groupsin Organic Synthesis,” by T. W. Greene and P. G. M. Wuts, Wiley, SecondEdition 1990, p. 223, to yield the BMD derivative, 76.1. The phosphonatemoiety is then introduced, using the procedures described below, toproduce the phosphonate ester, 76.2. The BMD moiety is then hydrolyzed,for example by treatment with 50% aqueous acetic acid, as described in“Protective Groups in Organic Synthesis,” by T. W. Greene and P. G. M.Wuts, Wiley, Second Edition 1990, p. 223, to afford the triol, 76.3.

Example 77

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino or iminoxy group and a variable carbon chain isillustrated above. In this procedure, the BMD-protected derivative,76.1, is reacted with an amine or hydroxylamine, 77.1, in which R² is analkyl, alkenyl, cycloalkyl or cycloalkenyl group, optionallyincorporating a heteroatom O, S or N, or a functional group such as anamide, ester, oxime, sulfoxide or sulfone etc, or an optionallysubstituted aryl, heteroaryl or aralkyl group, optionally incorporatinga heteroatom O, S or N, and X is either a phosphonate group or a groupwhich is subsequently converted into a phosphonate-containingsubstituent. For example, X is dialkylphosphono, bromo, hydroxy, amino,carboxy and the like. The reaction is conducted between equimolaramounts of the reactants in an aprotic solvent such as pyridine orxylene, or in an alcoholic solvent such as ethanol, optionally in thepresence of an acid catalyst, to give the imine or oxime. Thepreparation of oximes of steroidal 3-ketones is described in Anal.Bioch., 1978, 86, 133 and in J. Mass. Spectrom., 1995, 30, 497. TheBMD-protected side-chain compound, 77.2, is then converted, as describedin Scheme M1 in Example 76, into the triol, 77.3.

Example 77A

The preparation of hydroxylamine ethers incorporating a phosphonategroup is illustrated above. In this procedure, a phosphonate, 77.4, inwhich Lv is a leaving group such as bromo or trifluoromethylsulfonyloxy,is reacted with BOC-hydroxylamine, 77.5 (Aldrich), to produce the ether,77.6. The reaction is conducted between equimolar amounts of thereactants in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such as potassium hydroxideor dimethylaminopyridine. Deprotection, for example by treatment withtrifluoroacetic acid, then gives the hydroxylamine ether, 77.7.

Example 78

The preparation of phosphonates in which the phosphonate is attached bymeans of an iminoxy group. In this procedure, the substrate, 76.1, isreacted with a dialkyl phosphonomethyl hydroxylamine, 78.1, prepared asdescribed above from a dialkyl trifluoromethylsulfonyloxymethylphosphonate (Tetrahedron Lett., 1986, 27, 1477) and BOC-hydroxylamine,to afford the oxime, 78.2, which is deprotected to afford the triol,78.3. The oxime forming reaction is performed at ambient temperature inethanol-acetic acid solution between equimolar amounts of the reactants.

Using the above procedures, but employing, in place of the hydroxylamineether, 78.1, different oxime ethers, 77.1, the corresponding products,77.3 are obtained.

Example 79

The preparation of compounds in which the phosphonate group is attachedby means of a pyridyl methoxy group is illustrated above. In thisprocedure, the dienone, 76.1, is reacted, as described above, withO-(3-bromo-5-pyridylmethyl)hydroxylamine, 79.1, prepared as describedabove from 3-bromo-5-bromomethylpyridine (WO 95/28400), to give, afterdeprotection of the side-chain, the oxime, 79.2. The product is thenreacted, in the presence of a palladium catalyst, with a dialkylphosphite, 79.3, to afford the phosphonate, 79.4. The preparation ofarylphosphonates by means of a coupling reaction between aryl bromidesand dialkyl phosphites is described in J. Med. Chem., 1992, 35, 1371.The reaction is performed in an inert solvent such as toluene, in thepresence of a base such as triethylamine and a catalytic amount oftetrakis-(triphenylphosphine)palladium(0).

Alternatively, the bromo compound, 79.2, is coupled with a dialkylvinylphosphonate, 79.5 (Aldrich), to afford the phosphonate, 79.6. Thecoupling of aryl halides with olefins by means of the Heck reaction isdescribed, for example, in “Advanced Organic Chemistry,” by F. A. Careyand R. J. Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem. Res., 1979,12, 146. The aryl bromide and the olefin are coupled in a polar solventsuch as dimethylformamide or dioxan, in the presence of a palladium(0)catalyst such as tetrakis(triphenyl-phosphine)palladium(0) orpalladium(II) catalyst such as palladium(II) acetate, and optionally inthe presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product, 79.6, isreduced, for example by reaction with diimide, to produce the saturatedanalog, 79.7. The reduction of olefinic bonds is described in“Comprehensive Organic Transformations,” by R. C. Larock, VCH, 1989, p.6ff. The transformation is effected by means of catalytic hydrogenation,for example using a palladium on carbon catalyst and hydrogen or ahydrogen donor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of thebromopyridyloxy reagent, 79.1, different bromo-substituted aryl orheteroaryl alkoxy hydroxylamines, and/or different dialkyl alkenylphosphonates, the products analogous to the compounds, 79.4, 79.6 and79.7 are obtained.

Example 80

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino group is illustrated above. In this procedure, thesubstrate, 76.1, is reacted with a dialkyl 2-aminophenyl phosphonate,80.1, (Syn., 1999, 1368) to give, after deprotection, the imine product,80.2. The reaction is conducted in a hydrocarbon solvent such as tolueneor xylene, at reflux temperature, in the presence of a basic catalystsuch as sodium methoxide, or an acid catalyst such as p-toluenesulfonicacid, under azeotropic conditions. Using the above procedures, butemploying, in place of the 2-aminophenyl phosphonate, 80.1, differentamino-substituted aryl or heteroaryl phosphonates, products analogous to80.2 are obtained.

Example 81

The preparation of phosphonates in which the phosphonate is attached bymeans of an oximino group and an amide linkage is illustrated above. Inthis procedure, the dienone, 76.2, is reacted withO-(2-carboxyethyl)hydroxylamine, 81.1, (J. Med. Chem., 1990, 33, 1423)to yield the oxime, 81.2. The reaction of steroidal 1,4-dien-3-ones withsubstituted hydroxylamines is described in J. Steroid Bioch., 1976, 7,795; the reaction is performed between equimolar amounts of thereactants in a polar organic solvent such as pyridine or methanol,optionally in the presence of acetic acid or sodium acetate. The oximeis then reacted with a dialkyl methylaminomethyl phosphonate, 81.3, toyield the amide oxime, 81.4. The preparation of amides from carboxylicacids and derivatives is described, for example, in “Organic FunctionalGroup Preparations,” by S. R. Sandler and W. Karo, Academic Press, 1968,p. 274, and “Comprehensive Organic Transformations,” by R. C. Larock,VCH, 1989, p. 972ff. The carboxylic acid is reacted with the amine inthe presence of an activating agent, such as, for example,dicyclohexylcarbodiimide or diisopropylcarbodiimide, optionally in thepresence of, for example, hydroxybenztriazole, N-hydroxysuccinimide orN-hydroxypyridone, in a non-protic solvent such as, for example,pyridine, DMF or dichloromethane, to afford the amide.

Alternatively, the carboxylic acid is first converted into an activatedderivative such as the acid chloride, anhydride, mixed anhydride,imidazolide and the like, and then reacted with the amine, in thepresence of an organic base such as, for example, pyridine, to affordthe amide. The conversion of a carboxylic acid into the correspondingacid chloride is effected by treatment of the carboxylic acid with areagent such as, for example, thionyl chloride or oxalyl chloride in aninert organic solvent such as dichloromethane, optionally in thepresence of a catalytic amount of dimethylformamide.

The amide product, 81.4, is then converted, as described herein, intothe triol, 81.5.

Using the above procedures, but employing, in place of thehydroxylamine, 81.3, different carboxy-substituted hydroxylamines,and/or different amino-substituted phosphonates, the products analogousto 81.5 are obtained.

Example 82

The preparation of the phosphonate esters in which the phosphonate groupis attached to the 1′ or 2′ position of the pyrazole ring, by means ofan aromatic or heteroaromatic group, a heteroatom and a variable carbonchain is illustrated above. In this procedure, the BMD-protecteddienone, 76.1, is reduced to afford the 1,2-dihydro product, 82.1. Thecatalytic hydrogenation reaction is effected by the use oftris(triphenylphosphine)rhodium (I) chloride, for example as describedin J. Med. Chem., 2001, 44, 602. The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in J. Am. Chem. Soc., 1964,86, 1520, to afford the 2-formyl product, 82.2. This compound is thenreacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine, 82.3,wherein R² is alkyl, aralkyl, aryl or heteroaryl and in which thesubstituent X is either a phosphonate group or a group which issubsequently transformed into a phosphonate-containing substituent. Forexample, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and thelike. The reaction yields the isomeric 2′- and 1′-aryl pyrazoles, 82.4and 82.5. The pyrazole-forming reaction is performed between equimolaramounts of the reactants in an acidic solvent such as acetic acid, asdescribed in J. Am. Chem. Soc., 1964, 86, 1520. The pyrazoles, 82.4 and82.5, are then transformed, for example by the procedures describedherein, via the BMD-protected intermediates, 82.6 and 82.7, into thephosphonates, 82.8 and 82.9.

Example 83

The preparation of phosphonates in which the phosphonate is attached bymeans of a phenyl ring and an alkoxy or an acetylenic linkage isillustrated above. In this procedure, the ketoaldehyde, 82.2, isreacted, as described above, with 3-hydroxyphenylhydrazine, 83.1(Japanese Patent No. JP 03011081), to give the pyrazoles, 83.2 and 83.3.The 2′-substituted isomer, 83.2, is then reacted in dichloromethanesolution at ambient temperature with one molar equivalent oftrifluoromethylsulfonyl chloride and dimethylaminopyridine, to yield thetriflate, 83.4. The product is then reacted in toluene solution with adialkyl propynyl phosphonate, 83.5 (Syn., 1999, 2027), triethylamine anda catalytic amount of tetrakis(triphenylphosphine)palladium (0), to givethe acetylenic product, 83.6. The palladium-catalyzed coupling reactionof aryl triflates with terminal acetylenes is described in WO 02/30930.The BMD protecting group is then removed to yield the triol, 83.7.

Alternatively, the 1′-substituted pyrazole, 83.3, is reacted, in aMitsonobu reaction, with a dialkyl 2-hydroxyethyl phosphonate, 83.8(Epsilon), to afford the ether, 83.9. The preparation of aromatic ethersby means of the Mitsonobu reaction is described, for example, in“Comprehensive Organic Transformations,” by R. C. Larock, VCH, 1989, p.448, and in “Advanced Organic Chemistry,” Part B, by F. A. Carey and R.J. Sundberg, Plenum, 2001, p. 153-4 and in Org. React., 1992, 42, 335.The phenol and the alcohol component are reacted together in an aproticsolvent such as, for example, tetrahydrofuran, in the presence of adialkyl azodicarboxylate and a triarylphosphine, to afford the ether orthioether products. The procedure is also described in Org. React.,1992, 42, 335-656. The product, 83.9, is then deprotected to give thetriol, 83.10.

Using the above procedures, but employing different acetylenic orhydroxyl-substituted phosphonates, the products analogous to 83.7 and83.10 are obtained. The functionalization procedures are interchangeablebetween the pyrazole substrates, 83.2 and 83.3.

Example 84

The preparation of the phosphonates in which the phosphonate group isattached by means of a benzyl group and a saturated or unsaturatedcarbon chain is illustrated above. In this procedure, the ketoaldehyde,82.2, is reacted, as described above, with 3-bromobenzyl hydrazine, 84.1(U.S. Pat. No. 4,370,339), to produce the pyrazoles, 84.2 and 84.3. The1′-substituted isomer 84.2 is coupled, in the presence of a palladiumcatalyst, with a dialkyl vinylphosphonate, 84.4 (Aldrich), to give thephosphonate, 84.5. The product is then deprotected to afford the triol,84.6. Optionally, the styrenoid double bond present in the product,84.6, is reduced, as described above, to produce the saturated analog,84.7.

Alternatively, the 2′-substituted pyrazole, 84.3, is coupled, in thepresence of a palladium catalyst, with a dialkyl phosphite to preparethe phosphonate, 84.8, which is deprotected to give the triol, 84.9. Thepreparation of arylphosphonates by means of a coupling reaction betweenaryl bromides and dialkyl phosphites is described in J. Med. Chem.,1992, 35, 1371. This reaction is performed in an inert solvent such astoluene, in the presence of a base such as triethylamine andtetrakis(triphenylphosphine)palladium(0).

Using the above procedures, but employing, in place of the bromobenzylreagent, 84.1, different bromo-substituted aralkyl, aryl or heteroarylalkoxy hydrazines, and/or different dialkyl alkenyl phosphonates, theproducts analogous to the compounds, 84.6, 84.7 and 84.9 are obtained.

Example 85

The preparation of the phosphonate esters, 85.7 and 85.8, in which thephosphonate group is attached by means of a variable carbon linkage isillustrated above. In this procedure, the ketoaldehyde, 82.2, is reactedwith hydrazine, to afford the pyrazole derivative, 85.1. The reaction ofsteroidal 2-formyl-3-ketones with hydrazine is described in J. Am. Chem.Soc, 1964, 86, 1520. The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound, 85.2, in which R² and X are as defined above, to yield thealkylation products, 85.3 and 85.4. The alkylation of substitutedpyrazoles is described, for example, in “Heterocyclic Chemistry,” by T.L. Gilchrist, Longman, 1992, p. 309. The reaction is performed betweenequimolar amounts of the substrates in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts, 85.3 and 85.4, are, except in cases where X isdialkylphosphono, converted into the phosphonates, 85.5 and 85.6, usingthe procedures described herein, and deprotection then affords thetriols, 85.7 and 85.8.

Example 86

The pyrazole, 85.1, is reacted, as described above, with one molarequivalent of a dialkyl bromoacetonyl phosphonate, 86.1 (Tet., 1978, 34,649), to give the alkylated pyrazoles, 86.2 and 86.3. Deprotection thenyields the triols, 86.4 and 86.5.

Example 87

The pyrazole, 85.1, is reacted, as described above, with1,4-bis(bromo-methyl)benzene, 87.1, to give the pyrazoles, 87.2 and87.3. The products are subjected to an Arbuzov reaction, in which thebromomethyl substituent is converted into the dialkyl phosphonomethylsubstituent, by reaction with a trialkyl phosphite at 120°, to prepare,after deprotection of the side chain, the phosphonates, 87.4 and 87.5.The Arbuzov reaction is described in Handb. Organophosphorus Chem.,1992, 115-72. In the procedure, the substrate is heated at from 60° toabout 160° with a five to fifty-fold molar excess of the trialkylphosphite.

Using the above procedures, but employing, in place of the dibromide,87.1, different dibromides, the products analogous to 87.4 and 87.5 areobtained.

Example 88

A synthetic methodology towards the preparation of phosphonate compoundsof Formulae 88.1 and 88.2 is described by Westwood et al, J. Med. Chem.,1996, 39, 4608-4621, according to the general routes outlined below.

Example 89

The preparation of compounds of the invention having phosphonate groupsand intermediate compounds useful for their synthesis are illustratedbelow.

Example 90

The preparation of compounds of the invention having phosphonate groupsand intermediate compounds useful for their synthesis are illustratedbelow.

Example 91

The structures of Methylprednisolone suleptanate, 91A (WO 89/00558), andthe phosphonate esters, 91.1-91.3, are shown above in Example 91, inwhich the substituent R¹ is H, alkyl, alkenyl, aryl or aralkyl. Thecompounds, 91.1-91.3, incorporate a phosphonate moiety (R¹O)₂P(O)connected to the nucleus by means of a variable linking group,designated as “link” in the attached structures. The syntheses of thephosphonate compounds of this invention, 91.1-91.3, and of theintermediate compounds necessary for their synthesis are set forthbelow.

Methylprednisolone, 91.4, is reacted with paraformaldehyde and an acidcatalyst such as hydrochloric acid, as described in “Protective Groupsin Organic Synthesis,” by T. W. Greene and P. G. M. Wuts, Wiley, SecondEdition 1990, p. 223, to yield the BMD derivative, 91.5. The phosphonatemoiety is then introduced, using the procedures described herein, toproduce the phosphonate ester, 91.6. The BMD moiety is then hydrolyzed,for example by treatment with 50% aqueous acetic acid, as described in“Protective Groups in Organic Synthesis,” by T. W. Greene and P. G. M.Wuts, Wiley, Second Edition 1990, p. 223, to afford the triol, 91.7. Thetriol is then converted into the 21-suleptanate ester as described in WO89/00558. In this procedure, a mixed anhydride prepared by reactingsuleptanic acid with pivaloyl chloride, in the presence of a base suchas triethylamine, is reacted with the 21-hydroxy steroid, 91.7, toprepare the 21-suleptanate ester, 91.8.

Example 92

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino or iminoxy group and a variable carbon chain isillustrated above. In this procedure, the BMD-protected derivative,91.5, is reacted with an amine or hydroxylamine, 92.1, in which R² is analkyl, alkenyl, cycloalkyl or cycloalkenyl group, optionallyincorporating a heteroatom O, S or N, or a functional group such as anamide, ester, oxime, sulfoxide or sulfone etc, or an optionallysubstituted aryl, heteroaryl or aralkyl group, optionally incorporatinga heteroatom O, S or N, and X is either a phosphonate group or a groupwhich is subsequently converted into a phosphonate-containingsubstituent. For example, X is dialkylphosphono, bromo, hydroxy, amino,carboxy and the like. The reaction is conducted between equimolaramounts of the reactants in an aprotic solvent such as pyridine orxylene, or in an alcoholic solvent such as ethanol, optionally in thepresence of an acid catalyst, to give the imine or oxime. Thepreparation of oximes of steroidal 3-ketones is described in Anal.Bioch., 1978, 86, 133 and in J. Mass. Spectrom., 1995, 30, 497. TheBMD-protected side-chain compound, 92.2, is then converted into thetriol, 92.3, and then to the suleptanate, 92.4, as described above inExample 91.

Example 92A

The preparation of hydroxylamine ethers incorporating a phosphonategroup is illustrated above. In this procedure, a phosphonate, 92.5, inwhich Lv is a leaving group such as bromo or trifluoromethylsulfonyloxy.The phosphonate is reacted with BOC-hydroxylamine, 92.6 (Aldrich), toproduce the ether, 92.7. The reaction is conducted between equimolaramounts of the reactants in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such as potassium hydroxideor dimethylaminopyridine. Deprotection, for example by treatment withtrifluoroacetic acid, then gives the hydroxylamine ether, 92.8.

Example 93

The preparation of phosphonates in which the phosphonate is attached bymeans of an iminoxy group is illustrated above. In this procedure, thesubstrate, 91.5, is reacted with a dialkyl phosphonomethylhydroxylamine, 93.1, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tetrahedron Lett., 1986,27, 1477) and BOC-hydroxylamine, to afford the oxime, 93.4, which isdeprotected to afford the triol, 93.5, from which the suleptanate ester,93.6, is prepared. The oxime forming reaction is performed at ambienttemperature in ethanol-acetic acid solution between equimolar amounts ofthe reactants.

Using the above procedures, but employing, in place of the hydroxylamineether, 93.1, different oxime ethers, 92.1, the corresponding products,92.4 are obtained.

Example 94

The preparation of compounds in which the phosphonate group is attachedby means of a phenoxyethoxy oxime group is illustrated above. In thisprocedure, the dienone, 91.5, is reacted, as described above, withO-(3-bromo-phenoxyethyl)hydroxylamine, 94.1, prepared as described abovefrom 3-bromophenoxyethyl bromide (FR 1,481,052) and BOC-protectedhydroxyl-amine, to give, after deprotection of the side-chain, theoxime, 94.2. The product is then reacted, in the presence of a palladiumcatalyst, with a dialkyl phosphite, 94.3, to afford the phosphonate,94.4. The preparation of arylphosphonates by means of a couplingreaction between aryl bromides and dialkyl phosphites is described in J.Med. Chem., 1992, 35, 1371. The reaction is performed in an inertsolvent such as toluene, in the presence of a base such as triethylamineand a catalytic amount of tetrakis(triphenylphosphine)palladium(0). The21-hydroxy group is then converted into the 21-suleptanate product,94.5.

Alternatively, the bromo compound, 94.2, is coupled with a dialkylpropenylphosphonate, 94.6 (Aldrich), to afford the phosphonate, 94.7.The coupling of aryl halides with olefins by means of the Heck reactionis described, for example, in “Advanced Organic Chemistry,” by F. A.Carey and R. J. Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem. Res.,1979, 12, 146. The aryl bromide and the olefin are coupled in a polarsolvent such as dimethylformamide or dioxan, in the presence of apalladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0)or palladium(II) catalyst such as palladium(II) acetate, and optionallyin the presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product, 94.7, isreduced, for example by reaction with diimide, to produce the saturatedanalog, 94.9. The reduction of olefinic bonds is described in“Comprehensive Organic Transformations,” by R. C. Larock, VCH, 1989, p.6ff. The transformation is effected by means of catalytic hydrogenation,for example using a palladium on carbon catalyst and hydrogen or ahydrogen donor, or by the use of diimide or diborane. The products, 94.7and 94.9, are then converted into the suleptanate esters, 94.8 and94.10.

Using the above procedures, but employing, in place of thebromo-phenoxyethoxy reagent, 94.1, different bromo-substituted aryl orheteroaryl alkoxy hydroxylamines, and/or different dialkyl alkenylphosphonates, the products analogous to the compounds, 94.5, 94.8 and94.10 are obtained.

Example 95

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino group is illustrated above. In this procedure,compound, 91.5, is reacted with a dialkyl 4-aminophenyl phosphonate,95.1 (Epsilon), to give, after deprotection, the imine product, 95.2.The reaction is conducted in a hydrocarbon solvent such as toluene orxylene, at reflux temperature, in the presence of a basic catalyst suchas sodium methoxide, or an acid catalyst such as p-toluenesulfonic acid,under azeotropic conditions. The product is then converted into thesuleptanate ester, 95.3.

Using the above procedures, but employing, in place of the 4-aminophenylphosphonate, 95.1, different amino-substituted aryl or heteroarylphosphonates, products analogous to 95.3 are obtained.

Example 96

The preparation of phosphonates in which the phosphonate is attached bymeans of an oximino group and an amide linkage is illustrated above. Inthis procedure, the dienone, 91.5, is reacted withO-(4-aminobutyl)hydroxylamine, 96.1 (Pol. J. Chem., 1981, 55, 1163), toyield the oxime, 96.2. The reaction of steroidal 1,4-dien-3-ones withsubstituted hydroxylamines is described in J. Steroid Bioch., 1976, 7,795. The reaction is performed between equimolar amounts of thereactants in a polar organic solvent such as pyridine or methanol,optionally in the presence of acetic acid or sodium acetate. The oximeis then coupled with a dialkyl phosphonoacetic acid, 96.3 (Aldrich), toyield the amide oxime, 96.4. The preparation of amides from carboxylicacids and derivatives is described, for example, in “Organic FunctionalGroup Preparations,” by S. R. Sandler and W. Karo, Academic Press, 1968,p. 274, and “Comprehensive Organic Transformations,” by R. C. Larock,VCH, 1989, p. 972ff. The carboxylic acid is reacted with the amine inthe presence of an activating agent, such as, for example,dicyclohexylcarbodiimide or diisopropylcarbodiimide, optionally in thepresence of, for example, hydroxybenztriazole, N-hydroxysuccinimide orN-hydroxypyridone, in a non-protic solvent such as, for example,pyridine, DMF or dichloromethane, to afford the amide.

Alternatively, the carboxylic acid is first converted into an activatedderivative such as the acid chloride, anhydride, mixed anhydride,imidazolide and the like, and then reacted with the amine, in thepresence of an organic base such as, for example, pyridine, to affordthe amide. The conversion of a carboxylic acid into the correspondingacid chloride is effected by treatment of the carboxylic acid with areagent such as, for example, thionyl chloride or oxalyl chloride in aninert organic solvent such as dichloromethane, optionally in thepresence of a catalytic amount of dimethylformamide.

The amide product, 96.4, is then converted, as described herein, intothe suleptanate, 96.6.

Using the above procedures, but employing, in place of thehydroxylamine, 96.1, different amino-substituted hydroxylamines, and/ordifferent carboxy-substituted phosphonates, the products analogous to96.6 are obtained.

Example 97

The preparation of the phosphonate esters in which the phosphonate groupis attached to the 1′ or 2′ position of the pyrazole ring, by means ofan aromatic or heteroaromatic group, a heteroatom and a variable carbonchain is illustrated above. In this procedure, the BMD-protecteddienone, 91.5, is reduced to afford the 1,2-dihydro product, 97.1. Thecatalytic hydrogenation reaction is effected by the use oftris(triphenylphosphine)rhodium (I) chloride, for example as describedin J. Med. Chem., 2001, 44, 602. The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in J. Am. Chem. Soc., 1964,86, 1520, to afford the 2-formyl product, 97.2. This compound is thenreacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine, 97.3,wherein R² is alkyl, aralkyl, aryl or heteroaryl and in which thesubstituent X is either a phosphonate group or a group which issubsequently transformed into a phosphonate-containing substituent. Forexample, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and thelike. The reaction yields the isomeric 2′- and 1′-aryl pyrazoles, 97.4and 97.5. The pyrazole-forming reaction is performed between equimolaramounts of the reactants in an acidic solvent such as acetic acid, asdescribed in J. Am. Chem. Soc., 1964, 86, 1520. The pyrazoles, 97.4 and97.5, are then transformed, for example by the procedures described inExamples 98 and 99, via the BMD-protected intermediates, 97.6 and 97.7,into the phosphonate suleptanates, 97.9 and 97.11.

Example 98

The preparation of phosphonates in which the phosphonate is attached bymeans of a phenyl ring and an alkoxy or an alkenyl linkage isillustrated above. In this procedure, the ketoaldehyde, 97.2, isreacted, as described above, with 4-hydroxyphenylhydrazine, 98.1(Epsilon), to give the pyrazoles, 98.2 and 98.3. The 2′-substitutedisomer, 98.2, is then reacted in dimethylformamide solution at ambienttemperature with one molar equivalent of 1,4-dibromobut-2-ene anddimethylaminopyridine, to yield the bromoether, 98.4. The product isthen reacted at 120° in an Arbuzov reaction with a trialkyl phosphite,98.5, to give the phosphonate product, 98.6. The Arbuzov reaction, inwhich an alkyl bromide is transformed into the correspondingphosphonate, by heating at from 60° to about 150° with a trialkylphosphite, is described in Handb. Organophosphorus Chem., 1992, 115-72.The BMD protecting group is then removed and the product is acylated toyield the suleptanate ester triol, 98.8.

Alternatively, the 1′-substituted pyrazole, 98.3, is reacted, in aMitsonobu reaction, with a dialkyl 2-hydroxymethyl phosphonate, 98.9(Aldrich), to afford the ether, 98.10. The preparation of aromaticethers by means of the Mitsonobu reaction is described, for example, in“Comprehensive Organic Transformations,” by R. C. Larock, VCH, 1989, p.448, and in “Advanced Organic Chemistry,” Part B, by F. A. Carey and R.J. Sundberg, Plenum, 2001, p. 153-4 and in Org. React., 1992, 42, 335.The phenol and the alcohol or thiol component are reacted together in anaprotic solvent such as, for example, tetrahydrofuran, in the presenceof a dialkyl azodicarboxylate and a triaryl-phosphine, to afford theether or thioether products. The procedure is also described in Org.React., 1992, 42, 335. The product, 98.10, is then deprotected to givethe triol, 98.11, and the latter compound is acylated to afford thesuleptanate, 98.12.

Using the above procedures, but employing different dibromides orhydroxyl-substituted phosphonates, the products analogous to 98.8 and98.12 are obtained. The functionalization procedures are interchangeablebetween the pyrazole substrates, 98.2 and 98.3.

Example 991

The preparation of the phosphonates in which the phosphonate group isattached by means of a phenyl ring or a phenyl ring and a saturated orunsaturated carbon chain is illustrated above. In this procedure, theketo-aldehyde, 97.2, is reacted, as described above, with 4-bromophenylhydrazine, 99.1 (J. Organomet. Chem., 1999, 62, 581), to produce thepyrazoles, 99.2 and 99.3. The 1′-substituted isomer, 99.2, is coupled,in the presence of a palladium catalyst, with a dialkylvinylphosphonate, 99.4 (Aldrich), to give the phosphonate, 99.4a. Theproduct is then deprotected to afford the triol, 99.5, which isconverted into the suleptanate, 99.6. Optionally, the styrenoid doublebond present in the product, 99.6, is reduced, as described above, toproduce the saturated analog, 99.8.

Alternatively, the 2′-substituted pyrazole, 99.3, is coupled, in thepresence of a palladium catalyst, with a dialkyl phosphite to preparethe phosphonate, 99.9, which is deprotected, and the product is acylatedto give the suleptanate ester, 99.11. The preparation ofarylphosphonates by means of a coupling reaction between aryl bromidesand dialkyl phosphites is described in J. Med. Chem., 1992, 35, 1371.This reaction is performed in an inert solvent such as toluene, in thepresence of a base such as triethylamine andtetrakis-(triphenylphosphine)palladium(0).

Using the above procedures, but employing, in place of the bromophenylhydrazine, 99.1, different bromo-substituted aralkyl, aryl or heteroarylalkoxy hydrazines, and/or different dialkyl alkenyl phosphonates, theproducts analogous to the compounds, 99.6, 99.8 and 99.11 are obtained.

Example 100

The preparation of the phosphonate esters in which the phosphonate groupis attached by means of a variable carbon linkage is illustrated above.In this procedure, the ketoaldehyde, 97.2, is reacted with hydrazine, toafford the pyrazole derivative, 100.1. The reaction of steroidal2-formyl-3-ketones with hydrazine is described in J. Am. Chem. Soc,1964, 86, 1520. The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound, 100.2, in which R² and X are as defined above, to yield thealkylation products, 100.3 and 100.4. The alkylation of substitutedpyrazoles is described, for example, in “Heterocyclic Chemistry,” by T.L. Gilchrist, Longman, 1992, p. 309. The reaction is performed betweenequimolar amounts of the substrates in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts, 100.3 and 100.4 are, except in cases where X isdialkylphosphono, converted into the phosphonates, 100.1 and 100.6,using the procedures described herein, and deprotection/acylation thenaffords the suleptanate esters, 100.8 and 100.10.

Example 101

The pyrazole, 100.1, is reacted in tetrahydrofuran solution, asdescribed above, with one molar equivalent of a dialkyl bromobutylphosphonate, 101.1, (Synthesis, 1994, 9, 909) and lithiumhexamethyldisilazide to give the alkylated pyrazoles, 101.2 and 101.3.Deprotection/acylation then yields the suleptanates, 101.5 and 101.7.

Example 102

The pyrazole, 100.1, is reacted in tetrahydrofuran solution, asdescribed above, with 1,2-bis(bromomethyl)cyclopropane, 102.1 (Tet.,1997, 53, 10459), to give the pyrazoles, 102.2 and 102.3. The productsare subjected to an Arbuzov reaction, in which the bromomethylsubstituent is converted into the dialkyl phosphonomethyl substituent,by reaction with a trialkyl phosphite at 120°, to prepare, afterdeprotection of the side chain and acylation, the suleptanatephosphonates, 102.5 and 102.7. The Arbuzov reaction is described inHandb. Organophosphorus Chem., 1992, 115-72. In the procedure, thesubstrate is heated at from 60° to about 160° with a five to fifty-foldmolar excess of the trialkyl phosphite.

Using the above procedures, but employing, in place of the dibromide,102.1, different dibromides, the products analogous to 102.5 and 102.7are obtained.

Example 103

The structures of Clobetasol, 103A (U.S. Pat. No. 3,721,687), and thephosphonate esters, 103.1-103.3, are shown above. The compounds,103.1-103.3, incorporate a phosphonate moiety (R¹O)₂P(O) connected tothe nucleus by means of a variable linking group, designated as “link”in the attached structures.

A protection-deprotection sequence in which the steroid side-chain isprotected as a bis-methylenedioxy (BMD) moiety is illustrated above. Inthis sequence,9α-fluoro-16β-methyl-11β,17α,21-trihydroxypregn-1,4-dien-3,21-dione,103.4 (U.S. Pat. No. 3,721,687), is reacted with paraformaldehyde and anacid catalyst such as hydrochloric acid, as described in “ProtectiveGroups in Organic Synthesis,” by T. W. Greene and P. G. M. Wuts, Wiley,Second Edition 1990, p. 223, to yield the BMD derivative, 103.5. Thephosphonate moiety is then introduced, using the procedures describedbelow, to produce the phosphonate ester, 103.6. The BMD moiety is thenhydrolyzed, for example by treatment with 50% aqueous acetic acid, asdescribed in “Protective Groups in Organic Synthesis,” by T. W. Greeneand P. G. M. Wuts, Wiley, Second Edition 1990, p. 223, to afford thetriol, 103.7. The 21-hydroxy group is then converted into the 21-chlorogroup as described in U.S. Pat. No. 3,721,687, Chimia, 1992, 46, 338, orJ. Med. Chem., 1987, 30, 1581. In this procedure, the 21-hydroxysubstrate is reacted at about 0° with one molar equivalent ofmethanesulfonyl chloride in a basic solvent such as pyridine, to affordthe 21-mesylate, 103.8. The product is then reacted, indimethylformamide solution at about 70°, with ca. five molar equivalentsof lithium chloride, to yield the 21-chloro product, 103.9.

Example 104

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino or iminoxy group and a variable carbon chain isdescribed herein. In this procedure, the BMD-protected derivative,103.1, is reacted with an amine or hydroxylamine, 104.1, in which R² isan alkyl, alkenyl, cycloalkyl or cycloalkenyl group, optionallyincorporating a heteroatom O, S or N, or a functional group such as anamide, ester, oxime, sulfoxide or sulfone etc, or an optionallysubstituted aryl, heteroaryl or aralkyl group, optionally incorporatinga heteroatom O, S or N, and X is either a phosphonate group or a groupwhich is subsequently converted into a phosphonate-containingsubstituent. For example, X is dialkylphosphono, bromo, hydroxy, amino,carboxy and the like. The reaction is conducted between equimolaramounts of the reactants in an aprotic solvent such as pyridine orxylene, or in an alcoholic solvent such as ethanol, optionally in thepresence of an acid catalyst, to give the imine or oxime. Thepreparation of oximes of steroidal 3-ketones is described in Anal.Bioch., 1978, 86, 133 and in J. Mass. Spectrom., 1995, 30, 497. TheBMD-protected side-chain compound, 104.2, is then converted into thetriol, 104.3, and then to the 21-chloro product, 104.4, as describedherein.

Example 104A

The preparation of hydroxylamine ethers incorporating a phosphonategroup is illustrated above. In this procedure, a phosphonate, 104.5, inwhich Lv is a leaving group such as bromo or trifluoromethylsulfonyloxy,is reacted with BOC-hydroxylamine, 104.6 (Aldrich), to produce theether, 104.7. The reaction is conducted between equimolar amounts of thereactants in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such as potassium hydroxideor dimethylaminopyridine. Deprotection, for example by treatment withtrifluoroacetic acid, then gives the hydroxylamine ether, 104.8.

Example 105

The preparation of phosphonates in which the phosphonate is attached bymeans of an iminoxy group. In this procedure, the substrate, 103.1, isreacted with a dialkyl phosphonomethyl hydroxylamine, 105.1, prepared asdescribed above from a dialkyl trifluoromethylsulfonyloxymethylphosphonate (Tetrahedron Lett., 1986, 27, 1477) and BOC-hydroxylamine,to afford the oxime, 105.2. Deprotection then affords the triol, 105.3,from which the 21-chloro compound, 105.4, is prepared. The oxime formingreaction is performed at ambient temperature in ethanol-acetic acidsolution between equimolar amounts of the reactants. Using the aboveprocedures, but employing, in place of the hydroxylamine ether, 105.1,different oxime ethers, 104.1, the corresponding products, 105.4 areobtained.

Example 106

The preparation of compounds in which the phosphonate group is attachedby means of a 3-pyridylmethoxy oxime group described herein. In thisprocedure, the dienone, 103.1, is reacted, as described above, withO-(5-bromo-3-pyridylmethoxy)hydroxylamine, 106.1, prepared as describedabove from 5-bromo-3-bromomethylpyridine (WO 95/28400) and BOC-protectedhydroxyl-amine, to give, after deprotection of the side-chain, theoxime, 106.2. The product is then reacted, in the presence of apalladium catalyst, with a dialkyl phosphite, 106.3, to afford thephosphonate, 106.4. The preparation of arylphosphonates by means of acoupling reaction between aryl bromides and dialkyl phosphites isdescribed in J. Med. Chem., 1992, 35, 1371. The reaction is performed inan inert solvent such as toluene, in the presence of a base such astriethylamine and a catalytic amount oftetrakis(triphenylphosphine)-palladium(0). The 21-hydroxy group is thenconverted into the 21-chloro derivative, 106.5.

Alternatively, the bromo compound, 106.2, is coupled with a dialkyl4-vinylphenyl phosphonate, 106.6 (Macromolecules, 1998, 31, 2918), toafford the phosphonate, 106.7. The coupling of aryl halides with olefinsby means of the Heck reaction is described, for example, in “AdvancedOrganic Chemistry,” by F. A. Carey and R. J. Sundberg, Plenum, 2001, p.503ff and in Acc. Chem. Res., 1979, 12, 146. The aryl bromide and theolefin are coupled in a polar solvent such as dimethylformamide ordioxan, in the presence of a palladium(0) catalyst such astetrakis(triphenylphosphine)palladium(0) or palladium(II) catalyst suchas palladium(II) acetate, and optionally in the presence of a base suchas triethylamine or potassium carbonate. Optionally, the styrenoiddouble bond present in the product, 106.7, is reduced, for example byreaction with diimide, to produce the saturated analog, 106.9. Thereduction of olefinic bonds is described in “Comprehensive OrganicTransformations,” by R. C. Larock, VCH, 1989, p. 6ff. The transformationis effected by means of catalytic hydrogenation, for example using apalladium on carbon catalyst and hydrogen or a hydrogen donor, or by theuse of diimide or diborane. The products, 106.7 and 106.9, are thenconverted into the 21-chloro analogs, 106.8 and 106.10. Using the aboveprocedures, but employing, in place of the bromopyridyl-methoxy reagent,106.1, different bromo-substituted aryl or heteroaryl alkoxyhydroxylamines, and/or different dialkyl alkenyl phosphonates, theproducts analogous to the compounds, 106.5, 106.8 and 106.10 areobtained.

Example 107

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino group is illustrated above. In this procedure, thesubstrate, 103.1, is reacted with a dialkyl 4-aminobenzyl phosphonate,107.1, (Fluka) to give, after deprotection, the imine product, 107.2.The reaction is conducted in a hydrocarbon solvent such as toluene orxylene, at reflux temperature, in the presence of a basic catalyst suchas sodium methoxide, or an acid catalyst such as p-toluenesulfonic acid,under azeotropic conditions. The product is then converted into the21-chloro compound, 107.3.

Using the above procedures, but employing, in place of the 4-aminobenzylphosphonate, 107.1, different amino-substituted aryl or heteroarylphosphonates, products analogous to 107.3 are obtained.

Example 108

The preparation of phosphonates in which the phosphonate is attached bymeans of an oximino group and a thioether linkage is illustrated above.In this procedure, the dienone, 103.1, is reacted withO-(2-mercaptoethyl)hydroxyl-amine, 108.1 (Bioorganicheskaya Khim., 1986,12, 1662), to yield the oxime, 108.2. The reaction of steroidal1,4-dien-3-ones with substituted hydroxyl-amines is described in J.Steroid Bioch., 1976, 7, 795; the reaction is performed betweenequimolar amounts of the reactants in a polar organic solvent such aspyridine or methanol, optionally in the presence of acetic acid orsodium acetate. The product is then coupled, in a Mitsonobu reaction,with a dialkyl 3-hydroxy-phenyl phosphonate, 108.3 (Aurora), to yieldthe thioether oxime, 108.4. The preparation of aromatic ethers by meansof the Mitsonobu reaction is described, for example, in “ComprehensiveOrganic Transformations”, by R. C. Larock, VCH, 1989, p. 448, and in“Advanced Organic Chemistry,” Part B, by F. A. Carey and R. J. Sundberg,Plenum, 2001, p. 153-4 and in Org. React., 1992, 42, 335. The phenol andthe alcohol or thiol component are reacted together in an aproticsolvent such as, for example, tetrahydrofuran, in the presence of adialkyl azodicarboxylate and a triarylphosphine, to afford the ether orthioether products. The procedure is also described in Org. React.,1992, 42, 335-656. The thioether product, 108.4, is then hydrolyzed andconverted into the 21-chloro product, 108.6, as described in Example103.

Using the above procedures, but employing, in place of thehydroxyl-amine, 108.3, different hydroxy or mercapto-substitutedhydroxylamines, and/or different hydroxyaryl-substituted phosphonates,the products analogous to 108.6 are obtained.

Example 109

The preparation of the phosphonate esters in which the phosphonate groupis attached to the 1′ or 2′ position of the pyrazole ring, by means ofan aromatic or heteroaromatic group, a heteroatom and a variable carbonchain is illustrated above. In this procedure, the BMD-protecteddienone, 103.5, is reduced to afford the 1,2-dihydro product, 109.1. Thecatalytic hydrogenation reaction is effected by the use oftris(triphenylphosphine)rhodium (I) chloride, for example as describedin J. Med. Chem., 2001, 44, 602. The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in J. Am. Chem. Soc., 1964,86, 1520, to afford the 2-formyl product, 109.2. This compound is thenreacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine, 109.3,wherein R2 is alkyl, aralkyl, aryl or heteroaryl and in which thesubstituent X is either a phosphonate group or a group which issubsequently transformed into a phosphonate-containing substituent. Forexample, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl and thelike. The reaction yields the isomeric 2′- and 1′-aryl pyrazoles, 109.4and 109.5. The pyrazole-forming reaction is performed between equimolaramounts of the reactants in an acidic solvent such as acetic acid, asdescribed in J. Am. Chem. Soc., 1964, 86, 1520. The pyrazoles, 109.4 and109.5, are then transformed, for example by the procedures described inExamples 110 and 111, via the BMD-protected intermediates, 109.6 and109.7, into the 21-chloro phosphonates, 109.9 and 109.11.

Example 110

The preparation of the phosphonate esters in which the phosphonate groupis attached to the 1′ or 2′ position of the pyrazole ring, by means of acarbamate or an amino linkage is illustrated above. In this procedure,the ketoaldehyde, 109.2, is reacted, as described above, with3-aminophenyl-hydrazine 110.1 (EP 437105) to give the pyrazoles 110.2and 110.3. The 2′-substituted isomer 110.2 is then reacted indimethylformamide solution at ambient temperature with one molarequivalent of a dialkyl 2-hydroxyethyl phosphonate, 110.4 (Epsilon), andcarbonyl diimidazole, to yield the carbamate, 110.5. The preparation ofcarbamates is described in “Comprehensive Organic Functional GroupTransformations,” A. R. Katritzky, ed., Pergamon, 1995, Vol. 6, p 416ff,and in “Organic Functional Group Preparations,” by S. R. Sandler and W.Karo, Academic Press, 1986, p. 260ff. In the procedure, the amine isreacted in an inert aprotic solvent such as dichloromethane ortetrahydrofuran, with phosgene or a functional equivalent thereof, suchas carbonyl diimidazole, triphosgene, pentafluorophenyl carbonate andthe like, to afford the corresponding activated acylamine. The lattercompound is then reacted with an alcohol to yield the carbamate. The BMDprotecting group is then removed and the product is converted into the21-chloro product, 110.7.

Alternatively, the 1′-substituted pyrazole, 110.3, is reacted, in areductive amination reaction, with a dialkyl formylmethyl phosphonate,110.8 (Zh. Obschei. Khim., 1987, 57, 2793), and sodiumtriacetoxyborohydride, to afford the amine, 110.9. The preparation ofamines by means of reductive amination procedures is described, forexample, in “Comprehensive Organic Transformations,” by R. C. Larock,VCH, p 421, and in “Advanced Organic Chemistry,” Part B, by F. A. Careyand R. J. Sundberg, Plenum, 2001, p 269. In this procedure, the aminecomponent and the aldehyde or ketone component are reacted together inthe presence of a reducing agent such as, for example, borane, sodiumcyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminumhydride, optionally in the presence of a Lewis acid, such as titaniumtetraisopropoxide, as described in J. Org. Chem., 1990, 55, 2552. Theproduct, 110.9, is then deprotected to give the triol, 110.10, and thelatter compound is transformed into the 21-chloro analog, 110.11.

Using the above procedures, but employing different formyl orhydroxyl-substituted phosphonates, and/or different amino-substitutedhydrazines, the products analogous to 110.7 and 110.11 are obtained. Thefunctionalization procedures are interchangeable between the pyrazolesubstrates, 110.2 and 110.3.

Example 111

The preparation of the phosphonates in which the phosphonate group isattached by means of a phenyl ring and an amide linkage is illustratedabove. In this procedure, the ketoaldehyde, 109.2, is reacted, asdescribed above, with 3-carboxyphenyl hydrazine, 111.1 (Apin), toproduce the pyrazoles, 111.2 and 111.3. The 1′-substituted isomer,111.1, is coupled, in the presence of dicyclohexylcarbodiimide, with adialkyl 3-aminophenyl phosphonate, 111.4 (Aurora), to give the amide,111.5. The preparation of amides from carboxylic acids and derivativesis described, for example, in “Organic Functional Group Preparations,”by S. R. Sandler and W. Karo, Academic Press, 1968, p. 274, and“Comprehensive Organic Transformations,” by R. C. Larock, VCH, 1989, p.972ff. The carboxylic acid is reacted with the amine in the presence ofan activating agent, such as, for example, dicyclohexylcarbodiimide ordiisopropylcarbodiimide, optionally in the presence of, for example,hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxypyridone, in anon-protic solvent such as, for example, pyridine, DMF ordichloromethane, to afford the amide.

Alternatively, the carboxylic acid may first be converted into anactivated derivative such as the acid chloride, anhydride, mixedanhydride, imidazolide and the like, and then reacted with the amine, inthe presence of an organic base such as, for example, pyridine, toafford the amide.

The conversion of a carboxylic acid into the corresponding acid chloridecan be effected by treatment of the carboxylic acid with a reagent suchas, for example, thionyl chloride or oxalyl chloride in an inert organicsolvent such as dichloromethane, optionally in the presence of acatalytic amount of dimethylformamide.

The product is then deprotected to afford the triol, 111.6, which isconverted into the 21-chloro compound, 111.7.

Alternatively, the 2′-substituted pyrazole, 111.3, is coupled, asdescribed above, with a dialkyl methylaminomethyl phosphonate, 111.8, toprepare the amide phosphonate 111.9 which is deprotected, and theproduct is converted into the 21-chloro analog, 111.11.

Using the above procedures, but employing, in place of the carboxyphenylhydrazine, 111.1, different carboxy-substituted aralkyl, aryl orheteroaryl alkoxy hydrazines, and/or different dialkyl amino-substitutedphosphonates, the products analogous to the compounds, 111.7 and 111.11are obtained.

Example 112

The preparation of the phosphonate esters in which the phosphonate groupis attached by means of a variable carbon linkage is illustrated above.In this procedure, the ketoaldehyde, 109.2, is reacted with hydrazine,to afford the pyrazole derivative, 112.1. The reaction of steroidal2-formyl-3-ketones with hydrazine is described in J. Am. Chem. Soc,1964, 86, 1520. The reaction is performed in acetic acid at ambienttemperature. The pyrazole product is then reacted with a bromomethylcompound, 112.2, in which R² and X are as defined above, to yield thealkylation products, 112.3 and 112.4. The alkylation of substitutedpyrazoles is described, for example, in “Heterocyclic Chemistry,” by T.L. Gilchrist, Longman, 1992, p. 309. The reaction is performed betweenequimolar amounts of the substrates in a polar solvent such asdimethylformamide or tetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts, 112.3 and 112.4, are, except in cases where X isdialkylphosphono, converted into the phosphonates, 112.5 and 112.6,using the procedures described herein, and deprotection/acylation thenaffords the 21-chloro compounds, 112.8 and 112.10.

Example 113

The pyrazole, 112.1, is reacted in tetrahydrofuran solution, asdescribed above, with one molar equivalent of a dialkyl bromobutenylphosphonate, 113.1 (J. Med. Chem., 1992, 35, 1371), and lithiumhexamethyldisilazide to give the alkylated pyrazoles, 113.2 and 113.3.Deprotection followed by chlorination yields the 21-chloro products,113.5 and 113.7.

Example 114

The pyrazole, 112.1, is reacted in tetrahydrofuran solution, asdescribed above, with 1,4-dibromobut-2-yne, 114.1 (Aldrich), to give thepyrazoles, 114.2 and 114.3. The products are subjected to an Arbuzovreaction, in which the bromomethyl substituent is converted into thedialkyl phosphonomethyl substituent, by reaction with a trialkylphosphite at 120°, to prepare, after deprotection of the side chain andchlorination, the 21-chloro phosphonates, 114.5 and 114.7. The Arbuzovreaction is described in Handb. Organophosphorus Chem., 1992, 115-72. Inthe procedure, the substrate is heated at from 60° to about 160° with afive to fifty-fold molar excess of the trialkyl phosphite. Using theabove procedures, but employing, in place of the dibromide, 114.1,different dibromides, the products analogous to 114.5 and 114.7 areobtained.

Example 115

The preparation of compounds of the invention having phosphonate groupsand intermediate compounds useful for their synthesis are illustratedherein. A β-ketonitrile, 115.2, is generated from a phenylacetic acid,115.1, by condensation with a malononitrile ester under Claisenconditions. Reaction with hydroxylamine provides the 5-amino-1,2-oxazolewhich, upon condensation with cyanomorpholine provides the desiredSMP-114 analogs.

Example 116

The anisole derivative, 116.1, is demethylated by treatment with a Lewisacid such as boron tribromide. The resulting phenol is alkylated withE-1,4-dibromobutene and the resulting monobromide is heated withtriethylphosphite in a solvent such as toluene (or other Arbuzovreaction conditions: see Engel, R., “Synthesis of Carbon-phosphorusBonds,” CRC press, 1988) to generate the diethyl ester of the desiredphosphonic acid, 116.2. Saponification of the carboxylate ester givesthe phenylacetic acid ready for incorporation into the synthesis ofSMP-114 analogs.

Example 117

The preparation of compounds of the invention having phosphonate groupscan be prepared the procedure of Example 116 and substituting1,3-dibromopropane in place of the 1,4-dibromobutene.

Example 118

The free phenol in ethyl homovanillate, 118.1, is converted to the aryltriflate, and the biphenyl motif is generated by Suzuki coupling withphenyl-boronic acid (see Chem. Rev., 1995, 95, 2457). The remainingsteps are analogous to those described in Example 116.

Example 119

Ethyl 4-bromophenylacetate, 119.1, is coupled with4-methoxyphenyl-boronic acid using the Suzuki method (see above). Theremaining steps are analogous to those described in Example 116.

Example 120

6α,9α-Difluoro-16β-methyl-11β,17α,21-trihydroxypregn-1,4-dien-3,21-dione,120A, (U.S. Pat. No. 4,619,921) is reacted with paraformaldehyde and anacid catalyst such as hydrochloric acid, as described in “ProtectiveGroups in Organic Synthesis,” by T. W. Greene and P. G. M. Wuts, Wiley,Second Edition 1990, p. 223, to yield the BMD derivative, 120.1. Thephosphonate moiety is then introduced, using the procedures describedbelow, to produce the phosphonate ester 120.2. The BMD moiety is thenhydrolyzed, for example by treatment with 50% aqueous acetic acid, asdescribed in “Protective Groups in Organic Synthesis,” by T. W. Greeneand P. G. M. Wuts, Wiley, Second Edition 1990, p. 223, to afford thetriol, 120.3. The latter compound is then converted into the17,21-cyclic orthoester, 120.4, using the procedure described in Chem.Pharm. Bull., 1986, 34, 1613. The substrate is reacted indimethylformamide at 70° C. with two molar equivalents of triethylorthopropionate and a catalytic amount of p-toluenesulfonic acid. Theproduct is then reacted with an excess of trimethylsilyl chloride indimethylformamide at ambient temperature to produce the 21-chloro17-propionate product, 120.5.

Alternatively, the substrate, 120.3, is converted into the product,120.5, by means of the method described in J. Med. Chem., 1987, 30:1581. In this procedure, the 21-hydroxy group is activated by conversionto the 21-mesylate, by reaction with mesyl chloride in pyridine; themesylate group is then displaced to yield the 21-chloro intermediate, byreaction with lithium chloride in dimethylformamide, and the 17-hydroxylgroup is esterified to give the 21-chloro-17-propionate derivative,120.5. The selective acylation of the 17α hydroxyl group in the presenceof an 11β hydroxyl group is described in J. Med. Chem., 1987, 30: 1581.

Example 121

The BMD-protected derivative, 120.1, is reacted with an amine orhydroxylamine, 121.1, in which R² is an alkyl, alkenyl, cycloalkyl orcycloalkenyl group, optionally incorporating a heteroatom O, S or N, ora functional group such as an amide, ester, oxime, sulfoxide or sulfoneetc, or an optionally substituted aryl, heteroaryl or aralkyl group,optionally incorporating a heteroatom O, S or N, and X is either aphosphonate group or a group which is subsequently converted into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxy and the like. The reaction is conductedbetween equimolar amounts of the reactants in an aprotic solvent such aspyridine or xylene, or in an alcoholic solvent such as ethanol,optionally in the presence of an acid catalyst, to give the imine oroxime. The preparation of oximes of steroidal 3-ketones is described inAnal. Bioch., 1978, 86, 133 and in J. Mass. Spectrom., 1995, 30, 497.The BMD-protected side-chain compound, 121.2, is then converted into thetriol, 121.3, and then to the 21-chloro 17 propionate product, 121.4, asdescribed above.

The preparation of hydroxylamine ethers incorporating a phosphonategroup is illustrated above. A phosphonate, 121.5, in which Lv is aleaving group such as bromo or trifluoromethylsulfonyloxy, is reactedwith BOC-hydroxylamine, 121.6, (Aldrich) to produce the ether, 121.7.The reaction is conducted between equimolar amounts of the reactants ina polar solvent such as dimethylformamide or tetrahydrofuran, in thepresence of a base such as potassium hydroxide or dimethylaminopyridine.Deprotection, for example by treatment with trifluoroacetic acid, thengives the hydroxylamine ether, 121.8.

Example 122

The substrate, 120.1, is reacted with a dialkyl phosphonomethylhydroxylamine, 122.1, prepared as described above from a dialkyltrifluoro-ethylsulfonyloxymethyl phosphonate (Tet. Lett., 1986, 27:1477)and BOC-hydroxylamine, to afford the oxime, 122.2. Deprotection thenaffords the triol, 122.3, from which the 21-chloro 17-propionatecompound, 122.4, is prepared. The oxime forming reaction is performed atambient temperature in ethanol-acetic acid solution between equimolaramounts of the reactants.

Using the above procedures, but employing, in place of the hydroxylamineether, 122.1, different oxime ethers, 121.1, the corresponding products,121.4 are obtained.

Example 123

The dienone, 121.1, is reacted, as described above, withO-(4-bromo-2-thienylmethoxy)hydroxylamine, 123.1, prepared as describedabove from 4-bromo-2-bromomethylthiophene (WO 94/20456) andBOC-protected hydroxylamine, to give, after deprotection of theside-chain, the oxime, 123.2. The product is then reacted, in thepresence of a palladium catalyst, with a dialkyl phosphate, 123.3, toafford the phosphonate, 123.4. The preparation of arylphosphonates bymeans of a coupling reaction between aryl bromides and dialkylphosphites is described in J. Med. Chem. 1992, 35, 1371. The reaction isperformed in an inert solvent such as toluene, in the presence of a basesuch as triethylamine and a catalytic amount oftetrakis(triphenylphosphine)-palladium(0). The 21-hydroxy compound,123.4, is then converted, as described herein, into the 21-chloro17-propionate derivative, 123.5.

Alternatively, the bromo compound, 123.2, is coupled with a dialkylbutenyl phosphonate, 123.6, (Org. Lett., 2001, 3, 217) to afford thephosphonate, 123.7. The coupling of aryl halides with olefins by meansof the Heck reaction is described, for example, in F. A. Carey and R. J.Sundberg, Advanced Organic Chemistry, 503ff (Plenum, 2001) and in Acc.Chem. Res., 1979, 12, 146. The aryl bromide and the olefin are coupledin a polar solvent such as dimethylformamide or dioxan, in the presenceof a palladium(0) catalyst such astetrakis(triphenylphosphine)palladium(0) or palladium(II) catalyst suchas palladium(II) acetate, and optionally in the presence of a base suchas triethylamine or potassium carbonate. Optionally, the double bondpresent in the product, 123.7, is reduced, for example by reaction withdiimide, to produce the saturated analog, 123.9. The reduction ofolefinic bonds is described in R. C. Larock, Comprehensive OrganicTransformations, 6ff (VCH 1989). The transformation is effected by meansof catalytic hydrogenation, for example using a palladium on carboncatalyst and hydrogen or a hydrogen donor, or by the use of diimide ordiborane. The products, 123.7 and 123.9, are then converted into the21-chloro 17-propionate analogs, 123.8 and 123.10.

Using the above procedures, but employing, in place of thebromothienylmethoxy reagent, 123.1, different bromo-substituted aryl orheteroaryl alkoxy hydroxylamines, and/or different dialkyl alkenylphosphonates, the products analogous to the compounds, 123.5, 123.8 and123.10 are obtained.

Example 124

The substrate, 121.1, is reacted with a dialkyl 4-amino-2-thienylphosphonate, 124.1, prepared by the palladium-catalyzed coupling, asdescribed above, between 4-amino-2-bromothiophene (Tet., 1987, 43, 3295)and a dialkyl phosphite, to give, after deprotection, the imine product,124.2. The imine forming reaction is conducted in a hydrocarbon solventsuch as toluene or xylene, at reflux temperature, in the presence of abasic catalyst such as sodium methoxide, or an acid catalyst such asp-toluenesulfonic acid, under azeotropic conditions. The product is thenconverted into the 21-chloro 17-propionate compound, 124.3.

Using the above procedures, but employing, in place of the4-aminothienyl phosphonate, 124.1 different amino-substituted aryl orheteroaryl phosphonates, products analogous to 124.3 are obtained.

Example 125

The dienone, 121.1, is reacted with O-(4-aminobutyl)hydroxylamine,125.1, (Pol. J. Chem., 1981, 55, 1163) to yield the oxime, 125.2. Thereaction of steroidal 1,4-dien-3-ones with substituted hydroxylamines isdescribed in J. Steroid Bioch., 1976, 7, 795; the reaction is performedbetween equimolar amounts of the reactants in a polar organic solventsuch as pyridine or methanol, optionally in the presence of acetic acidor sodium acetate. The product is then coupled with a dialkyl2-hydroxyethyl phosphonate, 125.3, (Epsilon) and carbonyl diimidazole,to yield the carbamate oxime, 125.4. The preparation of carbamates isdescribed in A. R. Katritzky, Comprehensive Organic Functional GroupTransformations, 6, 416ff (Pergamon, 1995), and in S. R. Sandler and W.Karo, Organic Functional Group Preparations, 260ff (Academic Press,1986). In the procedure, the amine is reacted in an inert aproticsolvent such as dichloromethane or tetrahydrofuran, with phosgene or afunctional equivalent thereof, such as carbonyl diimidazole,triphosgene, pentafluorophenyl carbonate and the like, to afford thecorresponding activated acylamine. The latter compound is then reactedwith an alcohol to yield the carbamate. The carbamate product, 125.4, isthen converted, as described herein, into the 21-chloro 17-propionateproduct, 125.6.

Using the above procedures, but employing, in place of thehydroxylamine, 125.3, different amino-substituted hydroxylamines, and/ordifferent hydroxy-substituted phosphonates, the products analogous to125.6 are obtained.

Example 126

The BMD-protected dienone, 121.1, is reduced to afford the 1,2-dihydroproduct, 126.1. The catalytic hydrogenation reaction is effected by theuse of tris(triphenylphosphine)rhodium (I) chloride, for example asdescribed in J. Med. Chem., 2001, 44, 602. The product is then reactedwith ethyl formate and a base such as sodium hydride, in an inertsolvent such as toluene or dimethylformamide, as described in J. Am.Chem. Soc., 1964, 86, 1520, to afford the 2-formyl product, 126.2. Thiscompound is then reacted with an alkyl, aralkyl, aryl or heteroarylhydrazine, 126.3, in which the substituent X is either a phosphonategroup or a group which is subsequently transformed into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxyl and the like. The reaction yields theisomeric 2′- and 1′-aryl pyrazoles, 126.4 and 126.5. Thepyrazole-forming reaction is performed between equimolar amounts of thereactants in an acidic solvent such as acetic acid, as described in J.Am. Chem. Soc., 1964, 86, 1520. The pyrazoles, 126.4 and 126.5, are thentransformed, for example by the procedures described in Examples 122 and123, via the BMD-protected intermediates, 126.6 and 126.7, into the21-chloro 17-propionate phosphonates, 126.9 and 126.11.

Example 127

The ketoaldehyde, 126.2, is reacted, as described above, with3-carboxypropyl hydrazine, 127.1, (Ind. J. Exp. Biol., 1994, 32, 218) togive the pyrazoles, 127.2 and 127.3. The 2′-substituted isomer, 127.2,is then reacted in dimethylformamide solution at ambient temperaturewith one molar equivalent of a dialkyl 4-aminophenyl phosphonate, 127.4,(Epsilon) and dicyclohexyl carbodiimide, to yield the amide, 127.5. Thepreparation of amides from carboxylic acids and derivatives isdescribed, for example, in S. R. Sandler and W. Karo, Organic FunctionalGroup Preparations, 274 (Academic Press, 1968), and R. C. Larock,Comprehensive Organic Transformations, 972ff (VCH, 1989). The carboxylicacid is reacted with the amine in the presence of an activating agent,such as, for example, dicyclohexylcarbodiimide ordiisopropylcarbodiimide, optionally in the presence of, for example,hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxypyridone, in anon-protic solvent such as, for example, pyridine, DMF ordichloromethane, to afford the amide.

Alternatively, the carboxylic acid may first be converted into anactivated derivative such as the acid chloride, anhydride, mixedanhydride, imidazolide and the like, and then reacted with the amine, inthe presence of an organic base such as, for example, pyridine, toafford the amide.

The conversion of a carboxylic acid into the corresponding acid chloridecan be effected by treatment of the carboxylic acid with a reagent suchas, for example, thionyl chloride or oxalyl chloride in an inert organicsolvent such as dichloromethane, optionally in the presence of acatalytic amount of dimethylformamide. The BMD protecting group is thenremoved and the product is converted into the 21-chloro 17-propionateproduct, 127.7.

The 1′-substituted pyrazole, 127.3, is coupled, as described above, witha dialkyl aminomethyl phosphonate, 127.8 (Interchim), to afford theamide, 127.9. The product, 127.9, is then deprotected to give the triol,127.10, and the latter compound is transformed into the 21-chloro17-propionate, 127.11.

Using the above procedures, but employing different amino-substitutedphosphonates, and/or different carboxy-substituted hydrazines, theproducts analogous to 127.7 and 127.11 are obtained. Thefunctionalization procedures are interchangeable between the pyrazolesubstrates, 127.2 and 127.3.

Example 128

The ketoaldehyde, 126.2, is reacted, as described above, with allylhydrazine, 128.1, (Zh. Org. Khim., 1967, 3, 983) to produce thepyrazoles, 128.2 and 128.3. The 1′-substituted isomer, 128.2, iscoupled, as described herein, with a dialkyl 3-bromophenyl phosphonate,128.4, (Epsilon) to give the phosphonate, 128.5. The product is thendeprotected to afford the triol, 128.6, which is converted into the21-chloro 17-propionate compound, 128.7.

The 2′-substituted pyrazole, 128.3, is coupled, as described above, witha dialkyl 5-bromo-2-thienyl phosphonate, 128.8, (Syn., 2003, 455) toprepare the phosphonate, 128.9, which is deprotected, and the product isconverted into the 21-chloro 17-propionate analog, 128.11.

Using the above procedures, but employing, in place of the propenylhydrazine, 128.1, different alkenyl hydrazines, and/or different dialkylbromo-substituted phosphonates, the products analogous to the compounds,128.7 and 128.11 are obtained.

Example 129

The ketoaldehyde, 126.2, is reacted with hydrazine, to afford thepyrazole derivative, 129.1. The reaction of steroidal 2-formyl-3-ketoneswith hydrazine is described in J. Am. Chem. Soc, 1964, 86, 1520. Thereaction is performed in acetic acid at ambient temperature. Thepyrazole product is then reacted with a bromomethyl compound, 129.2, inwhich R² and X are as defined above, to yield the alkylation products,129.3 and 129.4. The alkylation of substituted pyrazoles is described,for example, in T. L. Gilchrist, Heterocyclic Chemistry, 309 (Longman,1992). The reaction is performed between equimolar amounts of thesubstrates in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts, 129.3 and 129.4, are, except in cases where X isdialkylphosphono, converted into the phosphonates, 129.5 and 129.6,using the procedures described herein, anddeprotection/chlorination/acylation then affords the 21-chloro17-propionate compounds, 129.8 and 129.10.

Example 130

Following the procedure described in Example 129, the pyrazole, 129.1,is reacted with 2-bromobenzyl bromide, 130.1, to give the pyrazoles,130.2 and 130.3. The products are then coupled, as described above, witha dialkyl phosphite, to afford, after side-chain deprotection andmodification, as described herein, the 21-chloro 17 propionates, 130.5and 130.7.

Example 131

Following the procedure described in Example 129, the pyrazole, 129.1,is reacted in tetrahydrofuran solution with 4-bromomethyl cyclohexanone,131.1, (WO 97/37959) to give the alkylation products, 131.2 and 131.3.The 1′-substituted isomer, 131.2, is then reacted, in a reductiveamination reaction, with a dialkyl aminomethyl phosphonate, 131.8,(Interchim) and sodium cyanoborohydride, to yield, after deprotectionand side-chain modification, the 21-chloro 17-propionate, 131.5.

The preparation of amines by means of reductive amination procedures isdescribed, for example, in R. C. Larock, Comprehensive OrganicTransformations, 421 (VCH, 1989), and in F. A. Carey and R. J. Sundberg,Advanced Organic Chemistry, Part B, 269 (Plenum, 2001). In thisprocedure, the amine component and the aldehyde or ketone component arereacted together in the presence of a reducing agent such as, forexample, borane, sodium cyanoborohydride, sodium triacetoxyborohydrideor diisobutylaluminum hydride, optionally in the presence of a Lewisacid, such as titanium tetraisopropoxide, as described in J. Org. Chem.,1990, 55, 2552.

The 2′-substituted pyrazole, 131.3, is subjected to the same series ofreaction to give the amine phosphonate, 131.7.

Using the above procedures, but employing differentbromomethyl-substituted aldehydes or ketones, and/or differentamino-substituted phosphonates, the products analogous to 131.5 and131.7 are obtained.

Example 132

A protection-deprotection sequence in which the 20-ketone group ofCliclesonide, 132A, (U.S. Pat. No. 5,482,934) is protected to afford thederivative, 132.1. The ketone is protected, for example, by conversionto the cyclic ethylene ketal, by reaction in toluene solution at refluxtemperature with ethylene glycol and an acid catalyst, as described inJ. Am. Chem. Soc., 1955, 77, 1904. Deprotection is effected by reactionwith pyridinium tosylate in aqueous acetone, as described in J. Chem.Soc. Chem. Comm., 1987, 1351.

Alternatively, the 20-ketone is protected by conversion to theN,N-dimethylhydrazone. The dimethyl hydrazone is prepared by thereaction of the ketone, 132A, with N,N-dimethylhydrazine inethanol-acetic acid, as described in Org. Syn., 1970, 50, 102. The groupis removed by treatment with sodium acetate and acetic acid in aqueoustetrahydrofuran, as described in J. Am. Chem. Soc., 1979, 101, 5841.

Alternatively, the 20-ketone is protected as the diethylamine adduct. Inthis procedure, the substrate, 132A, is reacted with titaniumtetrakis(diethylamide), as described in J. Chem. Soc. Chem. Comm., 1983,406, to afford the adduct. The ketone is deprotected by reaction withwater in an aqueous organic solvent.

The protected compound, 132.1, is then converted into thephosphonate-containing analog, 132.2, using the procedures describedbelow, and the protecting group is then removed, as described above, togive the phosphonate, 132.3.

Example 133

The protected derivative, 133.1, is reacted with an amine orhydroxylamine, 133.2, in which R² is an alkyl, alkenyl, cycloalkyl orcycloalkenyl group, optionally incorporating a heteroatom O, S or N, ora functional group such as an amide, ester, oxime, sulfoxide or sulfoneetc, or an optionally substituted aryl, heteroaryl or aralkyl group,optionally incorporating a heteroatom O, S or N, and X is either aphosphonate group or a group which is subsequently converted into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxy and the like. The reaction is conductedbetween equimolar amounts of the reactants in an aprotic solvent such aspyridine or xylene, or in an alcoholic solvent such as ethanol,optionally in the presence of an acid catalyst, to give the imine oroxime, 133.3. The preparation of oximes of steroidal 3-ketones isdescribed in Anal. Bioch., 1978, 86, 133 and in J. Mass. Spectrom.,1995, 30, 497. The protecting group is then removed, as describedherein, to afford the 20-keto phosphonate product, 133.4.

Example 133A

The preparation of hydroxylamine ethers incorporating a phosphonategroup is illustrated herein. In this procedure, a phosphonate, 133.5, inwhich Lv is a leaving group such as bromo or trifluoromethylsulfonyloxy,is reacted with BOC-hydroxylamine, 133.6, (Aldrich) to produce theether, 133.7. The reaction is conducted between equimolar amounts of thereactants in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such as potassium hydroxideor dimethylaminopyridine. Deprotection, for example by treatment withtrifluoroacetic acid, then gives the hydroxylamine ether, 133.8. Theabove procedure is also employed for the preparation of substitutedhydroxylamines which are precursors to phosphonates.

Example 134

The substrate, 133.1, in which the 20-ketone is protected as thedimethyl hydrazone derivative, is reacted with a dialkyl phosphonomethylhydroxylamine, 133.8, prepared as described above from a dialkyltrifluoromethylsulfonyl-oxymethyl phosphonate (Tetrahedron Lett., 1986,27, 1477) and BOC-hydroxylamine, to afford the oxime, 134.2.Deprotection, as described in Example 132, then affords the 20-ketophosphonate, 134.3. The oxime forming reaction is performed at ambienttemperature in ethanol-acetic acid solution between equimolar amounts ofthe reactants.

Using the above procedures, but employing, in place of the hydroxylamineether, 133.8, different oxime ethers, 133.2, the corresponding products,133.4 are obtained.

Example 135

The dienone, 133.1, in which the 20-ketone is protected as the dimethylhydrazone, is reacted, as described above, withO-(4-bromobenzyloxy)-hydroxylamine, 135.1, prepared as described abovefrom 4-bromobenzyl bromide and BOC-protected hydroxylamine, 133.6, togive the oxime, 135.2. The protecting group is then removed to yield the20-keto product, 135.3. The latter product is then reacted, in thepresence of a palladium catalyst, with a dialkyl phosphate, 135.4, toafford the phosphonate, 135.5. The preparation of arylphosphonates bymeans of a coupling reaction between aryl bromides and dialkylphosphites is described in J. Med. Chem., 1992, 35, 1371. The reactionis performed at ca. 100° C. in an inert solvent such as toluene, in thepresence of a base such as triethylamine and a catalytic amount oftetrakis(triphenyl-phosphine)palladium(0).

Alternatively, the bromo compound, 135.3, is coupled with a dialkylvinyl phosphonate, 135.6, (Aldrich) to afford the phosphonate, 135.7.The coupling of aryl halides with olefins by means of the Heck reactionis described, for example, in F. A. Carey and R. J. Sundberg, AdvancedOrganic Chemistry 503ff (Plenum, 2001) and in Acc. Chem. Res., 1979, 12,146. The aryl bromide and the olefin are coupled in a polar solvent suchas dimethylformamide or dioxan, in the presence of a palladium(0)catalyst such as tetrakis(triphenyl-phosphine)palladium(0) orpalladium(II) catalyst such as palladium(II) acetate, and optionally inthe presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product, 135.7, isreduced, for example by reaction with diimide, to produce the saturatedanalog, 135.8. The reduction of olefinic bonds is described in R. C.Larock, Comprehensive Organic Transformations 6ff (VCH 1989). Thetransformation is effected by means of catalytic hydrogenation, forexample using a palladium on carbon catalyst and hydrogen or a hydrogendonor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of thebromobenzyl-oxy reagent, 135.1, different bromo-substituted aryl orheteroaryl alkoxy hydroxylamines, and/or different dialkyl alkenylphosphonates, products analogous to the compounds, 135.5, 135.7 and135.8 are obtained.

Example 136

The substrate, 133.1, in which the 20-ketone is protected as thedimethylhydrazone, is reacted with a dialkyl 4-amino-2-furylphosphonate, 136.1, prepared by the palladium catalyzed couplingreaction, as described above, between 4-amino-2-bromofuran (TetrahedronLett., 1987, 43, 3295) and a dialkyl phosphite, to give, afterdeprotection, the imine product, 136.2. The imine forming reaction isconducted in a hydrocarbon solvent such as toluene or xylene, at refluxtemperature, in the presence of a basic catalyst such as sodiummethoxide, or an acid catalyst such as p-toluenesulfonic acid, underazeotropic conditions.

Using the above procedures, but employing, in place of the4-amino-2-furyl phosphonate, 136.1, different amino-substituted aryl orheteroaryl phosphonates, products analogous to 136.2 are obtained.

Example 137

The dienone, 133.1, in which the 20-ketone is protected as thedimethyl-hydrazone, is reacted with O-(2-carboxyethyl)hydroxylamine,137.1, (J. Med. Chem., 1990, 33, 1423) to yield the oxime, 137.2. Thereaction of steroidal 1,4-dien-3-ones with substituted hydroxylamines isdescribed in J. Steroid Bioch., 1976, 7, 795; the reaction is performedbetween equimolar amounts of the reactants in a polar organic solventsuch as pyridine or methanol, optionally in the presence of acetic acidor sodium acetate. The product, 137.2, is then coupled with a dialkyl4-aminophenyl phosphonate, 137.3, (Epsilon) anddicyclohexylcarbodiimide, to yield, after deprotection the amide oxime,137.4. The preparation of amides from carboxylic acids and derivativesis described, for example, in S. R. Sandler and W. Karo, OrganicFunctional Group Preparations 274 (Academic Press, 1968) and R. C.Larock, Comprehensive Organic Transformations 972ff (VCH, 1989). Thecarboxylic acid is reacted with the amine in the presence of anactivating agent, such as, for example, dicyclohexyl-carbodiimide ordiisopropylcarbodiimide, optionally in the presence of, for example,hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxypyridone, in anon-protic solvent such as, for example, pyridine, DMF ordichloromethane, to afford the amide.

Alternatively, the carboxylic acid may first be converted into anactivated derivative such as the acid chloride, anhydride, mixedanhydride, imidazolide and the like, and then reacted with the amine, inthe presence of an organic base such as, for example, pyridine, toafford the amide.

The conversion of a carboxylic acid into the corresponding acid chloridecan be effected by treatment of the carboxylic acid with a reagent suchas, for example, thionyl chloride or oxalyl chloride in an inert organicsolvent such as dichloromethane, optionally in the presence of acatalytic amount of dimethylformamide.

Using the above procedures, but employing, in place of thecarboxy-substituted hydroxylamine, 137.1, different carboxy-substitutedhydroxylamines, and/or different amino-substituted phosphonates,products analogous to 137.4 are obtained.

Example 138

The dienone, 132A, is reduced to afford the 1,2-dihydro product, 138.1.The catalytic hydrogenation reaction is effected by the use oftris(triphenyl-phosphine)rhodium (I) chloride, for example as describedin J. Med. Chem., 2001, 44, 602. The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in J. Am. Chem. Soc., 1964,86, 1520, to afford the 2-formyl product, 138.2. This compound is thenreacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine, 138.3, inwhich the substituent X is either a phosphonate group or a group whichis subsequently transformed into a phosphonate-containing substituent.For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl andthe like. The reaction yields the isomeric 2′- and 1′-aryl pyrazoles,138.4 and 138.5. The pyrazole-forming reaction is performed betweenequimolar amounts of the reactants in an acidic solvent such as aceticacid, as described in J. Am. Chem. Soc., 1964, 86, 1520. The pyrazoles,138.4 and 13.5, are then transformed, for example by the proceduresdescribed in Examples 139 and 140, into the phosphonates, 138.6 and138.7.

Example 139

The ketoaldehyde, 138.2, is reacted, as described above, with4-hydroxy-phenyl hydrazine, 139.1, (EP 437105) to give the pyrazoles,139.2 and 139.3. The 2′-substituted isomer, 139.2, is then reacted indimethylformamide solution at ca. 70° C. with a dialkyl bromobutenylphosphonate, 139.4, (J. Med. Chem., 1992, 35, 1371) and potassiumcarbonate, to yield the ether phosphonate, 139.5.

The isomeric pyrazole, 139.3, is reacted, in a Mitsonobu reaction, witha dialkyl mercaptomethyl phosphonate, 139.6, (J. Med. Chem., 1985, 26,1688) to yield the thioether phosphonate, 139.7. The preparation ofaromatic ethers and thioethers by means of the Mitsonobu reaction isdescribed, for example, in R. C. Larock, Comprehensive OrganicTransformations 448 (VCH, 1989), in F. A. Carey and R. J. Sundberg,Advanced Organic Chemistry, Part B 153-4 (Plenum, 2001), and in Org.React., 1992, 42, 335. The phenol and the alcohol or thiol component arereacted together in an aprotic solvent such as, for example,tetrahydrofuran, in the presence of a dialkyl azodicarboxylate and atriarylphosphine, to afford the ether or thioether products. Theprocedure is also described in Org. React., 1992, 42, 335-656.

Using the above procedures, but employing different hydroxy-substitutedhydrazines, and/or different bromo- or mercapto-substitutedphosphonates, products analogous to 139.5 and 139.7 are obtained.

Example 140

The ketoaldehyde, 138.2, is reacted, as described above, with4-aminophenyl hydrazine, 140.1, (Epsilon) to produce the pyrazoles,140.2 and 140.3. The 2′-substituted isomer, 140.2, is coupled, asdescribed above, with a dialkyl phosphonoacetic acid, 140.4, (Aldrich)and dicyclohexyl carbodiimide, to give the amide phosphonate, 140.5.

Alternatively, the 1′-substituted pyrazole, 140.3, is reacted with adialkyl 3-hydroxypropyl phosphonate, 140.6, (Zh. Obschei. Khim., 1973,43, 2364), and carbonyl diimidazole to prepare the carbamatephosphonate, 140.7. The preparation of carbamates is described inComprehensive Organic Functional Group Transformations, Vol. 6, 416ff(A. R. Katritzky, ed., Pergamon, 1995) and in S. R. Sandler and W. Karo,Organic Functional Group Preparations 260ff (Academic Press, 1986). Inthe procedure, the amine is reacted in an inert aprotic solvent such asdichloromethane or tetrahydrofuran, with phosgene or a functionalequivalent thereof, such as carbonyl diimidazole, triphosgene,pentafluorophenyl carbonate and the like, to afford the correspondingactivated acylamine. The latter compound is then reacted with an alcoholto yield the carbamate.

Using the above procedures, but employing, in place of the4-amino-1-phenyl hydrazine, 140.1, different amino-substitutedhydrazines, and/or different dialkyl carboxy or hydroxy-substitutedphosphonates, products analogous to the compounds, 140.5 and 140.7 areobtained.

Example 141

The ketoaldehyde, 138.2, is reacted with hydrazine, to afford thepyrazole derivative, 141.1. The reaction of steroidal 2-formyl-3-ketoneswith hydrazine is described in J. Am. Chem. Soc., 1964, 86, 1520. Thereaction is performed in acetic acid at ambient temperature. Thepyrazole product is then reacted with a bromomethyl compound, 141.2, inwhich R² and X are as defined above, or a reactive bromoheteroaromaticreagent, to yield the alkylation products, 141.3 and 141.4. Thealkylation of substituted pyrazoles is described, for example, in T. L.Gilchrist, Heterocyclic Chemistry 309 (Longman, 1992). The reaction isperformed between equimolar amounts of the substrates in a polar solventsuch as dimethylformamide or tetrahydrofuran, in the presence of a basesuch as dimethylaminopyridine, lithium hexamethyldisilazide and thelike. The products, 141.3 and 141.4, are, except in cases where X isdialkyl-phosphono, converted into the phosphonates, 141.5 and 141.6,using the procedures described herein.

Example 142

The pyrazole, 141.1, is reacted, as described above, with a dialkylacetonyl phosphonate, 142.1, (Tetrahedron Lett., 1978, 34, 649) to givethe pyrazoles, 141.2 and 141.3.

Example 143

The pyrazole, 141.1, is reacted in tetrahydrofuran solution, with2,5-bis(bromomethyl)thiophene, 143.1, (Tetrahedron Lett., 1999, 55,4709) and potassium hexamethyl disilazide, to give the alkylationproducts, 143.2 and 143.3. The 2′-substituted isomer, 143.2, is thenreacted, in a Arbuzov reaction, with a trialkyl phosphite to yield thephosphonate, 143.4. The Arbuzov reaction is described in Handb.Organophosphorus Chem., 1992, 115. In this procedure, in which a bromosubstituent is converted into the corresponding phosphonate, thesubstrate is heated at from about 60° C. to about 160° C. with a five tofifty-fold molar excess of a trialkyl phosphite, to effect thetransformation.

The 2′-substituted pyrazole, 143.3, is reacted at 70° C. indimethylformamide solution with one molar equivalent of a dialkyl3-aminophenyl phosphonate, 143.5, and cesium carbonate, to give theamine phosphonate, 143.6.

Using the above procedures, but employing different dibromides, and/ordifferent amino-substituted phosphonates, products analogous to 143.4and 143.6 are obtained.

Example 144

A protection-deprotection sequence in which the 20-ketone group ofDeflazacort, 144A, (U.S. Pat. No. 3,436,389) is protected to afford thederivative, 144.1, as shown. The ketone is protected, for example, byconversion to the cyclic ethylene ketal, by reaction in toluene solutionat reflux temperature with ethylene glycol and an acid catalyst, asdescribed in J. Am. Chem. Soc., 1955, 77, 1904. Deprotection is effectedby reaction with pyridinium tosylate in aqueous acetone, as described inJ. Chem. Soc. Chem. Comm., 1987, 1351.

Alternatively, the 20-ketone is protected by conversion to theN,N-dimethylhydrazone. The dimethyl hydrazone is prepared by thereaction of the ketone, 144A, with N,N-dimethylhydrazine inethanol-acetic acid, as described in Org. Syn., 1970, 50, 102. The groupis removed by treatment with sodium acetate and acetic acid in aqueoustetrahydrofuran, as described in J. Am. Chem. Soc., 1979, 101, 5841.

Alternatively, the 20-ketone is protected as the diethylamine adduct. Inthis procedure, the substrate, 144A, is reacted with titaniumtetrakis(diethylamide), as described in J. Chem. Soc. Chem. Comm., 1983,406, to afford the adduct. The ketone is deprotected by reaction withwater in an aqueous organic solvent.

The protected compound, 144.1, is then converted into thephosphonate-containing analog, 144.2, using the procedures describedbelow, and the protecting group is then removed, as described above, togive the phosphonate, 144.3.

Example 145

The protected derivative, 145.1, is reacted with an amine orhydroxylamine, 145.2, in which R² is an alkyl, alkenyl, cycloalkyl orcycloalkenyl group, optionally incorporating a heteroatom O, S or N, ora functional group such as an amide, ester, oxime, sulfoxide or sulfoneetc, or an optionally substituted aryl, heteroaryl or aralkyl group,optionally incorporating a heteroatom O, S or N, and X is either aphosphonate group or a group which is subsequently converted into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxy and the like. The reaction is conductedbetween equimolar amounts of the reactants in an aprotic solvent such aspyridine or xylene, or in an alcoholic solvent such as ethanol,optionally in the presence of an acid catalyst, to give the imine oroxime, 145.3. The preparation of oximes of steroidal 3-ketones isdescribed in Anal. Bioch., 1978, 86, 133 and in J. Mass. Spectrom.,1995, 30, 497. The protecting group is then removed, as describedherein, to afford the 20-keto phosphonate product, 145.4.

Example 145A

The preparation of hydroxylamine ethers incorporating a phosphonategroup is illustrated herein. In this procedure, a phosphonate, 145.5, inwhich Lv is a leaving group such as bromo or trifluoromethylsulfonyloxy,is reacted with BOC-hydroxylamine, 145.6, (Aldrich) to produce theether, 145.7. The reaction is conducted between equimolar amounts of thereactants in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such as potassium hydroxideor dimethylaminopyridine. Deprotection, for example by treatment withtrifluoroacetic acid, then gives the hydroxylamine ether, 145.8. Theabove procedure is also employed for the preparation of substitutedhydroxylamines which are precursors to phosphonates.

Example 146

The substrate, 145.1, in which the 20-ketone is protected as thedimethyl hydrazone derivative, is reacted with a dialkyl phosphonomethylhydroxylamine, 146.1, prepared as described above from a dialkyltrifluoromethylsulfonyl-oxymethyl phosphonate (Tetrahedron Lett., 1986,27, 1477) and BOC-hydroxylamine, to afford the oxime, 146.2.Deprotection, as described in Example 144, then affords the 20-ketophosphonate, 146.3. The oxime forming reaction is performed at ambienttemperature in ethanol-acetic acid solution between equimolar amounts ofthe reactants.

Using the above procedures, but employing, in place of the hydroxylamineether, 146.1, different oxime ethers, 145.2, the corresponding products,145.4 are obtained.

Example 147

The dienone, 145.1, in which the 20-ketone is protected as the dimethylhydrazone, is reacted, as described above, withO-(3-bromophenylethoxy)-hydroxylamine, 147.1, prepared as describedabove from 3-bromophenylethyl bromide (French Patent FR 1481052), andBOC-protected hydroxylamine, 145.6, to give the oxime, 147.2. Theprotecting group is then removed to yield the 20-keto product, 147.3.The latter product is then reacted, in the presence of a palladiumcatalyst, with a dialkyl phosphate, 147.4, to afford the phosphonate,147.5. The preparation of arylphosphonates by means of a couplingreaction between aryl bromides and dialkyl phosphites is described in J.Med. Chem., 1992, 35, 1371. The reaction is performed at ca. 100° C. inan inert solvent such as toluene, in the presence of a base such astriethylamine and a catalytic amount oftetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo compound, 147.3, is coupled with a dialkylpropenyl phosphonate, 147.6, (Aldrich) to afford the phosphonate, 147.7.The coupling of aryl halides with olefins by means of the Heck reactionis described, for example, in F. A. Carey and R. J. Sundberg, AdvancedOrganic Chemistry 503ff (Plenum, 2001) and in Acc. Chem. Res., 1979, 12,146. The aryl bromide and the olefin are coupled in a polar solvent suchas dimethylformamide or dioxan, in the presence of a palladium(0)catalyst such as tetrakis(triphenyl-phosphine)palladium(0) orpalladium(II) catalyst such as palladium(II) acetate, and optionally inthe presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product, 147.7, isreduced, for example by reaction with diimide, to produce the saturatedanalog, 147.8. The reduction of olefinic bonds is described in R. C.Larock, Comprehensive Organic Transformations 6ff (VCH 1989). Thetransformation is effected by means of catalytic hydrogenation, forexample using a palladium on carbon catalyst and hydrogen or a hydrogendonor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of thebromophenylethyl reagent, 147.1, different bromo-substituted aryl orheteroaryl alkoxy hydroxylamines, and/or different dialkyl alkenylphosphonates, products analogous to the compounds, 147.5, 147.7 and147.8 are obtained.

Example 148

The substrate, 145.1, in which the 20-ketone is protected as thedimethylhydrazone, is reacted with a dialkyl 3-aminophenyl phosphonate,148.1, (J. Med. Chem., 1984, 27, 654), to give, after deprotection, theimine product, 148.2. The imine forming reaction is conducted in ahydrocarbon solvent such as toluene or xylene, at reflux temperature, inthe presence of a basic catalyst such as sodium methoxide, or an acidcatalyst such as p-toluenesulfonic acid, under azeotropic conditions.

Using the above procedures, but employing, in place of the 3-aminophenylphosphonate, 148.1, different amino-substituted aryl or heteroarylphosphonates, products analogous to 148.2 are obtained.

Example 149

The dienone, 145.1, in which the 20-ketone is protected as thedimethylhydrazone, is reacted with O-(2-hydroxyethyl)hydroxylamine,149.1, (J. Chem. Soc. Chem. Comm., 1986, 903) to yield the oxime, 149.2.The reaction of steroidal 1,4-dien-3-ones with substitutedhydroxylamines is described in J. Steroid Bioch., 1976, 7, 795; thereaction is performed between equimolar amounts of the reactants in apolar organic solvent such as pyridine or methanol, optionally in thepresence of acetic acid or sodium acetate. The product, 149.2, is thencoupled with a dialkyl 4-aminophenyl phosphonate, 149.3, (Epsilon) andcarbonyl diimidazole, to yield, after deprotection, the carbamate oxime,149.4. The preparation of carbamates is described in ComprehensiveOrganic Functional Group Transformations, Vol. 6, 416ff (A. R.Katritzky, ed., Pergamon, 1995) and in S. R. Sandler and W. Karo,Organic Functional Group Preparations 260ff (Academic Press, 1986). Inthe procedure, the amine is reacted in an inert aprotic solvent such asdichloromethane or tetrahydrofuran, with phosgene or a functionalequivalent thereof, such as carbonyl diimidazole, triphosgene,pentafluorophenyl carbonate and the like, to afford the correspondingactivated acylamine. The latter compound is then reacted with an alcoholto yield the carbamate.

Using the above procedures, but employing, in place of thehydroxy-substituted hydroxylamine, 149.1, different hydroxy-substitutedhydroxylamines, and/or different amino-substituted phosphonates, theproducts analogous to 149.4 are obtained.

Example 150

The dienone, 144A, is reduced to afford the 1,2-dihydro product, 150.1.The catalytic hydrogenation reaction is effected by the use oftris(triphenyl-phosphine)rhodium (I) chloride, for example, as describedin J. Med. Chem., 2001, 44, 602. The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in J. Am. Chem. Soc., 1964,86, 1520, to afford the 2-formyl product, 150.2. This compound is thenreacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine, 150.3, inwhich the substituent X is either a phosphonate group or a group whichis subsequently transformed into a phosphonate-containing substituent.For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl andthe like. The reaction yields the isomeric 2′- and 1′-aryl pyrazoles,150.4 and 150.5. The pyrazole-forming reaction is performed betweenequimolar amounts of the reactants in an acidic solvent such as aceticacid, as described in J. Am. Chem. Soc., 1964, 86, 1520. The pyrazoles,150.4 and 150.5, are then transformed, for example by the proceduresdescribed herein, into the phosphonates, 150.6 and 150.7.

Example 151

The ketoaldehyde, 150.2, is reacted, as described above, with3-carboxyphenyl hydrazine, 151.1, (Apin) to give the pyrazoles, 151.2and 151.3. The 2′-substituted isomer, 151.2, is then coupled indimethylformamide solution at ambient temperature with a dialkyl3-aminopropyl phosphonate, 151.4, (Acros) and dicyclohexyl carbodiimide,to yield the amide phosphonate, 151.5. The preparation of amides fromcarboxylic acids and derivatives is described, for example, in S. R.Sandler and W. Karo, Organic Functional Group Preparations 274 (AcademicPress, 1986), and R. C. Larock, Comprehensive Organic Transformations972ff (VCH, 1989). The carboxylic acid is reacted with the amine in thepresence of an activating agent, such as, for example,dicyclohexyl-carbodiimide or diisopropylcarbodiimide, optionally in thepresence of, for example, hydroxybenztriazole, N-hydroxysuccinimide orN-hydroxypyridone, in a non-protic solvent such as, for example,pyridine, DMF or dichloromethane, to afford the amide.

Alternatively, the carboxylic acid may first be converted into anactivated derivative such as the acid chloride, anhydride, mixedanhydride, imidazolide and the like, and then reacted with the amine, inthe presence of an organic base such as, for example, pyridine, toafford the amide.

The conversion of a carboxylic acid into the corresponding acid chloridecan be effected by treatment of the carboxylic acid with a reagent suchas, for example, thionyl chloride or oxalyl chloride in an inert organicsolvent such as dichloromethane, optionally in the presence of acatalytic amount of dimethylformamide.

The isomeric pyrazole, 151.3, is reacted, as described above, with adialkyl 2-aminophenyl phosphonate, 151.6, (Acros) to yield the amidephosphonate, 151.7.

Using the above procedures, but employing different carboxy-substitutedhydrazines, and/or different amino-substituted phosphonates, theproducts analogous to 151.5 and 151.7 are obtained.

Example 152

The ketoaldehyde, 150.2, is reacted, as described above, with1,3-bis(hydrazino)benzene, 152.1, (Bull. Soc. Chim. Fr., 1975, 1371) toproduce the pyrazoles, 152.2 and 152.3. The 2′-substituted isomer,152.2, is reacted in tetrahydrofuran solution at ambient temperaturewith one molar equivalent of a dialkylphosphono acetaldehyde (Aurora),to give the hydrazone phosphonate, 152.5.

Alternatively, the 1′-substituted pyrazole, 152.3, is coupled, asdescribed above, with a dialkylphosphono butyric acid, 152.6, (Epsilon)and dicyclohexyl carbodiimide to prepare the phosphonate, 152.7.

Using the above procedures, but employing, in place of the1,3-bis(hydrazino)phenyl hydrazine, 152.1, different bis hydrazines,and/or different dialkyl formyl or carboxy-substituted phosphonates, theproducts analogous to the compounds, 152.5 and 152.7 are obtained.

Example 153

The ketoaldehyde, 150.2, is reacted with hydrazine to afford thepyrazole derivative, 153.1. The reaction of steroidal 2-formyl-3-ketoneswith hydrazine is described in J. Am. Chem. Soc., 1964, 86, 1520. Thereaction is performed in acetic acid at ambient temperature. Thepyrazole product is then reacted with a bromomethyl compound 153.2, inwhich R² and X are as defined above, or a reactive bromoheteroaromaticreagent, to yield the alkylation products, 153.3 and 153.4. Thealkylation of substituted pyrazoles is described, for example, in T. L.Gilchrist, Heterocyclic Chemistry 309 (Longman, 1992). The reaction isperformed between equimolar amounts of the substrates in a polar solventsuch as dimethylformamide or tetrahydrofuran, in the presence of a basesuch as dimethylaminopyridine, lithium hexamethyldisilazide and thelike. The products, 153.3 and 153.4, are, except in cases where X isdialkylphosphono, converted into the phosphonates, 153.5 and 153.6,using the procedures described herein.

Example 154

The pyrazole, 153.1, is reacted in dimethylformamide solution at 70° C.with one molar equivalent of a dialkyl bromopropyl phosphonate, 154.1,(Synthelec) and cesium carbonate, to give the pyrazoles, 154.2 and154.3.

Example 155

The pyrazole, 153.1, is reacted in tetrahydrofuran solution with1,4-bis(bromomethyl)benzene, 155.1, and potassium hexamethyl disilazide,to give the alkylation products, 155.2 and 155.3. The 2′-substitutedisomer, 155.2, is then reacted, in an Arbuzov reaction, with a trialkylphosphite to yield the phosphonate, 155.4. The Arbuzov reaction isdescribed in Handb. Organophosphorus Chem., 1992, 115. In thisprocedure, in which a bromo substituent is converted into thecorresponding phosphonate, the substrate is heated at from about 60° C.to about 160° C. with a five to fifty-fold molar excess of a trialkylphosphite, to effect the transformation.

The 2′-substituted-pyrazole, 155.3, is reacted at 70° C. indimethyl-formamide solution with one molar equivalent of a dialkylmercaptoethyl phosphonate, 155.5, (Zh. Obschei. Khim., 1973, 43, 2364)and cesium carbonate, to give the thioether phosphonate, 155.6.

Using the above procedures, but employing different dibromides, and/ordifferent mercapto-substituted phosphonates, products analogous to 155.4and 155.6 are obtained.

Example 156

Medroxyprogesterone, 156A, (U.S. Pat. Nos. 3,043,832, 3,061,616, and3,377,364) is protected to afford the derivative, 156.1. The ketone isprotected, for example, by conversion to the cyclic ethylene ketal, byreaction in toluene solution at reflux temperature with ethylene glycoland an acid catalyst, as described in J. Am. Chem. Soc., 1955, 77, 1904.Deprotection is effected by reaction with pyridinium tosylate in aqueousacetone, as described in as described in J. Chem. Soc. Chem. Comm.,1987, 1351.

Alternatively, the 20-ketone is protected by conversion to theN,N-dimethylhydrazone. The dimethyl hydrazone is prepared by thereaction of the ketone, 156A, with N,N-dimethylhydrazine inethanol-acetic acid, as described in Org. Syn., 1970, 50, 102. The groupis removed by treatment with sodium acetate and acetic acid in aqueoustetrahydrofuran, as described in J. Am. Chem. Soc., 1979, 101, 5841.

Alternatively, the 20-ketone is protected as the diethylamine adduct. Inthis procedure, the substrate, 156A, is reacted with titaniumtetrakis(diethylamide), as described in J. Chem. Soc. Chem. Comm., 1983,406, to afford the adduct. The ketone is deprotected by reaction withwater in an aqueous organic solvent.

The protected compound, 156.1, is then converted into thephosphonate-containing analog, 156.2, using the procedures describedbelow, and the protecting group or groups are then removed, as describedabove, to give the phosphonate, 156.3.

Example 157

The ketone-protected derivative, 156.1, is reacted with a hydroxylamineor amine, 157.1, in which R² is an alkyl, alkenyl, cycloalkyl orcycloalkenyl group, optionally incorporating a heteroatom O, S or N, ora functional group such as an amide, ester, oxime, sulfoxide or sulfone,etc., or an optionally substituted aryl, heteroaryl or aralkyl group,optionally incorporating a heteroatom O, S or N, and X is either aphosphonate group or a group which is subsequently converted into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxy and the like. The reaction is conductedbetween equimolar amounts of the reactants in an aprotic solvent such aspyridine or xylene, or in an alcoholic solvent such as ethanol,optionally in the presence of an acid catalyst, to give the oxime,157.2. The preparation of oximes of steroidal 3-ketones is described inAnal. Bioch. 1978, 86, 133 and in J. Mass. Spectrom. 1995, 30, 497. Theprotecting group is then removed, as described in Example 156, to affordthe 20-keto phosphonate product, 157.3.

Example 157A

The preparation of hydroxylamine ethers incorporating a phosphonategroup is illustrated herein. A phosphonate, 157.4, in which Lv is aleaving group such as bromo or trifluoromethylsulfonyloxy, is reactedwith BOC-hydroxyl-amine, 157.5, (Aldrich) to produce the ether, 157.6.The reaction is conducted between equimolar amounts of the reactants ina polar solvent such as dimethylformamide or tetrahydrofuran, in thepresence of a base such as potassium hydroxide or dimethylaminopyridine.Deprotection, for example by treatment with trifluoroacetic acid, thengives the hydroxylamine ether, 157.7. The above procedure is alsoemployed for the preparation of substituted hydroxylamines which areprecursors to phosphonates.

Example 158

The preparation of phosphonates, in which the phosphonate is attached bymeans of an iminoxy group is illustrated herein. In this procedure, thesubstrate, 156.1, in which the 20-ketone is protected as the dimethylhydrazone derivative, is reacted with a dialkyl phosphonomethylhydroxylamine, 158.1, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tetrahedron Lett., 1986,27, 1477) and BOC-hydroxylamine, to afford the oxime, 158.2.Deprotection, as described in Example 156, then affords the 20-ketophosphonate, 158.3. The oxime forming reaction is performed at ambienttemperature in ethanol-acetic acid solution between equimolar amounts ofthe reactants.

Using the above procedures, but employing, in place of thehydroxyl-amine ether, 158.1, different oxime ethers, 157.1, thecorresponding products, 157.3 are obtained.

Example 159

The dienone, 156.1, in which the 20-ketone is protected as the dimethylhydrazone, is reacted, as described above, withO-(5-bromo-3-pyridylmethoxy)-hydroxylamine, 159.1, prepared as describedabove from 5-bromo-3-bromo-methylpyridine (WO 95/28400) andBOC-protected hydroxylamine, 157.5, to give the oxime, 159.2. Theprotecting group is then removed to yield the 20-keto product, 159.3.The latter product is then reacted, in the presence of a palladiumcatalyst, with a dialkyl phosphite, 159.4, to afford the phosphonate,159.5. The preparation of arylphosphonates by means of a couplingreaction between aryl bromides and dialkyl phosphites is described in J.Med. Chem., 1992, 35, 1371. The reaction is performed at ca. 100° C. inan inert solvent such as toluene, in the presence of a base such astriethylamine and a catalytic amount oftetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo compound, 159.3, is coupled with a dialkylvinylphosphonate, 159.6, (Aldrich) to afford the phosphonate, 159.7. Thecoupling of aryl halides with olefins by means of the Heck reaction isdescribed, for example, in F. A. Carey and R. J. Sundberg, AdvancedOrganic Chemistry 503ff (Plenum, 2001) and in Acc. Chem. Res., 1979, 12,146. The aryl bromide and the olefin are coupled in a polar solvent suchas dimethylformamide or dioxan, in the presence of a palladium(0)catalyst such as tetrakis(triphenyl-phosphine)palladium(0) orpalladium(II) catalyst such as palladium(II) acetate, and optionally inthe presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product, 159.7, isreduced, for example by reaction with diimide, to produce the saturatedanalog, 159.8. The reduction of olefinic bonds is described in R. C.Larock, Comprehensive Organic Transformations 6ff (VCH 1989). Thetransformation is effected by means of catalytic hydrogenation, forexample using a palladium on carbon catalyst and hydrogen or a hydrogendonor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of the bromopyridylreagent, 159.1, different bromo-substituted aryl or heteroaryl alkoxyhydroxylamines, and/or different dialkyl alkenyl phosphonates, productsanalogous to the compounds, 159.5, 159.7 and 159.8 are obtained.

Example 160

The dienone, 156.1, in which the 20-ketone is protected as thedimethylhydrazone, is reacted with 2-hydroxyethyl hydroxylamine, 160.1,(J. Chem. Soc. Chem. Comm., 1986, 903) to yield the oxime, 160.2. Thereaction of unsaturated steroidal ketones with hydroxylamines isdescribed in J. Steroid Bioch. 1976, 7, 795; the reaction is performedbetween equimolar amounts of the reactants in a polar organic solventsuch as pyridine or methanol, optionally in the presence of acetic acidor sodium acetate. The product, 160.2, is then coupled with a dialkyl4-aminophenyl phosphonate, 160.3, (Epsilon) and carbonyl diimidazole, toyield, after deprotection, the carbamate oxime, 160.4. The preparationof carbamates is described in Comprehensive Organic Functional GroupTransformations, Vol. 6, 416ff (A. R. Katritzky, ed., Pergamon, 1995)and in S. R. Sandler and W. Karo, Organic Functional Group Preparations260ff (Academic Press, 1986). In the procedure, the amine is reacted inan inert aprotic solvent such as dichloromethane or tetrahydrofuran,with phosgene or a functional equivalent thereof, such as carbonyldiimidazole, triphosgene, pentafluorophenyl carbonate and the like, toafford the corresponding activated acylamine. The latter compound isthen reacted with an alcohol to yield the carbamate.

Using the above procedures, but employing, in place of thehydroxy-substituted hydroxylamine, 160.1, different hydroxy-substitutedhydroxylamines, and/or different amino-substituted phosphonates, theproducts analogous to 160.4 are obtained.

Example 161

The enone, 161.1, in which the 20-ketone is protected as the cyclicethylene ketal, is reacted with ethyl formate and a base such as sodiumhydride, in an inert solvent such as toluene or dimethylformamide, asdescribed in J. Am. Chem. Soc. 86:1520 (1964), to afford the 2-formylproduct, 161.2. This compound is then reacted with an alkyl, aralkyl,aryl or heteroaryl hydrazine, 161.3, in which the substituent X iseither a phosphonate group or a group which is subsequently transformedinto a phosphonate-containing substituent. For example, X isdialkylphosphono, bromo, hydroxy, amino, carboxyl and the like. Thereaction yields, after deprotection of the 20-ketone, the isomeric 2′-and 1′-aryl pyrazoles, 161.4 and 161.5. The pyrazole-forming reaction isperformed between equimolar amounts of the reactants in an acidicsolvent such as acetic acid, as described in J. Am. Chem. Soc., 1964,86, 1520. The pyrazoles, 161.4 and 161.5, are then transformed, forexample by the procedures described herein, into the phosphonates, 161.6and 161.7.

Example 162

The ketoaldehyde, 161.2, is reacted, as described above, with3-carboxyphenyl hydrazine, 162.1, (Apin) to give the pyrazoles, 162.2and 162.3. The 2′-substituted isomer, 162.2, is then reacted indimethylformamide solution at ambient temperature with one molarequivalent of a dialkyl 2-aminoethyl phosphonate, 162.4, (Aldrich) anddicyclohexyl carbodiimide, to give the amide phosphonate, 162.5. Thepreparation of amides from carboxylic acids and derivatives isdescribed, for example, in S. R. Sandler and W. Karo, Organic FunctionalGroup Preparations 274 (Academic Press, 1968) and R. C. Larock,Comprehensive Organic Transformations 972ff (VCH, 1989). The carboxylicacid is reacted with the amine in the presence of an activating agent,such as, for example, dicyclohexylcarbodiimide ordiisopropylcarbodiimide, optionally in the presence of, for example,hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxypyridone, in anon-protic solvent such as, for example, pyridine, DMF ordichloromethane, to afford the amide.

Alternatively, the carboxylic acid may first be converted into anactivated derivative such as the acid chloride, anhydride, mixedanhydride, imidazolide and the like, and then reacted with the amine, inthe presence of an organic base such as, for example, pyridine, toafford the amide.

The conversion of a carboxylic acid into the corresponding acid chloridecan be effected by treatment of the carboxylic acid with a reagent suchas, for example, thionyl chloride or oxalyl chloride in an inert organicsolvent such as dichloromethane, optionally in the presence of acatalytic amount of dimethylformamide.

The isomeric pyrazole, 162.3, is reacted, as described above, with onemolar equivalent of a dialkyl 4-amino-2-thienyl phosphonate, 162.6,prepared by the palladium catalyzed coupling reaction, as describedabove, between 4-amino-2-bromothiophene (Tetrahedron Lett., 1987, 43,3295) and a dialkyl phosphite, to give the amide phosphonate, 162.7.

Using the above procedures, but employing different carboxy-substitutedhydrazines, and/or different amino-substituted phosphonates, theproducts analogous to 162.5 and 162.7 are obtained.

Example 163

The ketoaldehyde, 161.2, is reacted, as described above, with3-bromophenyl hydrazine, 163.1, (Fluka) to produce the pyrazoles, 163.2and 163.3. The 2′-substituted isomer, 163.2, is then coupled, asdescribed above, with a dialkyl phosphite, 163.4, to afford thephosphonate, 163.5.

Alternatively, the 1′-substituted pyrazole, 163.3, is coupled, asdescribed above, with a dialkyl vinylphosphonate, 163.6, (Aldrich) and apalladium catalyst to prepare the vinyl phosphonate, 163.7. Optionally,the product is reduced, as described above, to give the analog, 163.8.

Using the above procedures, but employing, in place of the bromophenylhydrazine, 163.1, different bromo-substituted hydrazines, and/ordifferent dialkyl alkenyl phosphonates, the products analogous to thecompounds, 163.5 and 163.7, 163.8 are obtained.

Example 164

The ketoaldehyde, 161.2, is reacted with hydrazine to afford, afterdeprotection of the 20-ketone, the pyrazole derivative, 164.1. Thereaction of steroidal 2-formyl-3-ketones with hydrazine is described inJ. Am. Chem. Soc., 1964, 86, 1520. The reaction is performed in aceticacid at ambient temperature. The pyrazole product is then reacted with abromomethyl compound, 164.2, in which R² and X are as defined above, ora reactive bromoheteroaromatic reagent, to yield the alkylationproducts, 164.3 and 164.4. The alkylation of substituted pyrazoles isdescribed, for example, in T. L. Gilchrist, Heterocyclic Chemistry, 309(Longman, 1992). The reaction is performed between equimolar amounts ofthe substrates in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such asdimethylaminopyridine, lithium hexamethyldisilazide and the like. Theproducts, 164.3 and 164.4, are, except in cases where X isdialkylphosphono, converted into the phosphonates, 164.5 and 164.6,using the procedures described herein.

Example 165

The pyrazole, 164.1, is reacted in dimethylformamide solution at 70° C.with one molar equivalent of a dialkyl 4-bromomethyl phosphonate, 165.1,(Lancaster) and lithium hexamethyl disilazide, to give the pyrazoles,165.2 and 165.3.

Using the above procedures, but employing different bromo-substitutedphosphonates, the products analogous to 165.2 and 165.3 are obtained.

Example 166

The pyrazole, 164.1, is reacted in tetrahydrofuran solution with4-bromomethyl cyclohexanone, 166.1, (WO 97/37959) and potassiumhexamethyl disilazide, to give the alkylation products, 166.2 and 166.3.The 2′-substituted isomer, 166.2, is then reacted, in a reductiveamination reaction, with a dialkyl aminomethyl phosphonate, 166.5,(Interchim) and sodium triacetoxy borohydride, to yield the aminephosphonate, 166.4. The preparation of amines by means of reductiveamination procedures is described, for example, in R. C. Larock,Comprehensive Organic Transformations 421 (VCH) and in F. A. Carey andR. J. Sundberg, Advanced Organic Chemistry, Part B, 269 (Plenum, 2001).In this procedure, the amine component and the aldehyde or ketonecomponent are reacted together in the presence of a reducing agent suchas, for example, borane, sodium cyanoborohydride, sodiumtriacetoxyborohydride or diisobutylaluminum hydride, optionally in thepresence of a Lewis acid, such as titanium tetraisopropoxide, asdescribed in J. Org. Chem., 1990, 55, 2552.

The 1′-substituted pyrazole, 166.3, is converted by the same reactioninto the isomeric amine phosphonate, 166.6.

Using the above procedures, but employing different bromo-substitutedaldehydes and ketones, and/or different amino-substituted phosphonates,products analogous to 166.4 and 166.6 are obtained.

Example 167

9α-Chloro-16α-methyl-11β,17α,21-trihydroxypregn-1,4-dien-3,2,1-dione,167A, (U.S. Pat. No. 4,472,393) is reacted with paraformaldehyde and anacid catalyst such as hydrochloric acid, as described in ProtectiveGroups in Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley,Second Edition 1990, p. 223, to yield the BMD derivative, 167.1. Thephosphonate moiety is then introduced, using the procedures describedbelow, to produce the phosphonate ester, 167.2. The BMD moiety is thenhydrolyzed, for example by treatment with 50% aqueous acetic acid, asdescribed in Protective Groups in Organic Synthesis, by T. W. Greene andP. G. M. Wuts, Wiley, Second Edition 1990, p. 223, to afford the triol,167.3. The latter compound is then converted into the 17,21-cyclicorthoester, 167.5, using the procedure described in Chem. Pharm. Bull.,1986, 34, 1613. The substrate is reacted in dimethylformamide at 70° C.with two molar equivalents of triethyl ortho-2-furoate, 165.4, (Zh. Org.Khim., 1980, 50, 1348) and a catalytic amount of p-toluenesulfonic acid.The product is then reacted with an excess of trimethylsilyl chloride indimethylformamide at ambient temperature to produce the 21-chloro17-(2-furoate) product, 167.6.

Alternatively, the substrate, 167.3, is converted into the product,167.6, by means of the method described in J. Med. Chem., 1987, 30,1581. In this procedure, the 21-hydroxy group is activated by conversionto the 21-mesylate, by reaction with mesyl chloride in pyridine; themesylate group is then displaced to yield the 21-chloro intermediate, byreaction with lithium chloride in dimethylformamide, and the 17-hydroxylgroup is esterified to give the 21-chloro-17-(2-furoate) derivative,167.6. The selective acylation of the 17α-hydroxyl group in the presenceof an 11β hydroxyl group is described in J. Med. Chem., 1987, 30, 1581.

Example 168

The BMD-protected derivative, 167.1, is reacted with an amine orhydroxylamine, 168.1, in which R² is an alkyl, alkenyl, cycloalkyl orcycloalkenyl group, optionally incorporating a heteroatom O, S or N, ora functional group such as an amide, ester, oxime, sulfoxide or sulfoneetc, or an optionally substituted aryl, heteroaryl or aralkyl group,optionally incorporating a heteroatom O, S or N, and X is either aphosphonate group or a group which is subsequently converted into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxy and the like. The reaction is conductedbetween equimolar amounts of the reactants in an aprotic solvent such aspyridine or xylene, or in an alcoholic solvent such as ethanol,optionally in the presence of an acid catalyst, to give the imine oroxime. The preparation of oximes of steroidal 3-ketones is described inAnal Bioch., 1978, 86, 133 and in J. Mass. Spectrom., 1995, 30, 497. TheBMD-protected side-chain compound, 168.2, is then converted into thetriol, 168.3, and then to the 21-chloro 17-(2-furoate) product, 168.4,as described herein.

The preparation of hydroxylamine ethers incorporating a phosphonategroup is illustrated herein. In this procedure, a phosphonate, 168.5, inwhich Lv is a leaving group such as bromo or trifluoromethylsulfonyloxy,is reacted with BOC-hydroxylamine, 168.6, (Aldrich) to produce theether, 168.7. The reaction is conducted between equimolar amounts of thereactants in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such as potassium hydroxideor dimethylaminopyridine. Deprotection, for example by treatment withtrifluoroacetic acid, then gives the hydroxylamine ether, 168.8.

Example 169

The substrate, 167.1, is reacted with a dialkyl phosphonomethylhydroxylamine, 169.1, prepared as described above from a dialkyltrifluoromethylsulfonyloxymethyl phosphonate (Tet. Lett., 1986, 27,1477) and BOC-hydroxylamine, to afford the oxime, 169.2. Deprotectionthen affords the triol, 169.3, from which the 21-chloro 17-(2-furoate)compound, 169.4, is prepared, using the procedures described in Example167. The oxime forming reaction is performed at ambient temperature inethanol-acetic acid solution between equimolar amounts of the reactants.

Using the above procedures, but employing, in place of the hydroxylamineether, 169.1, different oxime ethers, 167.1, the corresponding products,169.4 are obtained.

Example 170

The dienone, 167.1, is reacted, as described above, withO-(5-bromo-3-pyridylmethoxy)hydroxylamine, 170.1, prepared as describedabove from 5-bromo-3-bromomethylpyridine (EP 511865) and BOC-protectedhydroxylamine, 168.6, to give, after deprotection of the side-chain, theoxime, 170.2. The product is then reacted, in the presence of apalladium catalyst, with a dialkyl phosphite, 170.3, to afford thephosphonate, 170.4. The preparation of arylphosphonates by means of acoupling reaction between aryl bromides and dialkyl phosphites isdescribed in J. Med. Chem., 1992, 35, 1371. The reaction is performed atca. 100° C. in an inert solvent such as toluene, in the presence of abase such as triethylamine and a catalytic amount oftetrakis(triphenyl-phosphine)palladium(0). The 21-hydroxy compound,170.4, is then converted, as described in Example 167, into the21-chloro 17-(2-furoate) derivative, 170.5.

Alternatively, the bromo compound, 170.2, is coupled with a dialkylvinyl phosphonate, 170.6, (Aldrich) to afford the phosphonate, 170.7.The coupling of aryl halides with olefins by means of the Heck reactionis described, for example, in F. A. Carey and R. J. Sundberg, AdvancedOrganic Chemistry, 503ff (Plenum, 2001) and in Acc. Chem. Res., 1979,12, 146. The aryl bromide and the olefin are coupled in a polar solventsuch as dimethylformamide or dioxan, in the presence of a palladium(0)catalyst such as tetrakis(triphenyl-phosphine)palladium(0) orpalladium(II) catalyst such as palladium(II) acetate, and optionally inthe presence of a base such as triethylamine or potassium carbonate.Optionally, the double bond present in the product, 170.7, is reduced,for example by reaction with diimide, to produce the saturated analog,170.9. The reduction of olefinic bonds is described in R. C. Larock,Comprehensive Organic Transformations, 6ff (VCH, 1989). Thetransformation is effected by means of catalytic hydrogenation, forexample using a palladium on carbon catalyst and hydrogen or a hydrogendonor, or by the use of diimide or diborane. The products, 170.7 and170.9, are then converted into the 21-chloro 17-(2-furoate) analogs,170.8 and 170.10.

Using the above procedures, but employing, in place of thebromopyridylmethoxy reagent, 170.1, different bromo-substituted aryl orheteroaryl alkoxy hydroxylamines, and/or different dialkyl alkenylphosphonates, the products analogous to the compounds, 170.5, 170.8 and170.10 are obtained.

Example 171

The preparation of phosphonates in which the phosphonate is attached bymeans of an imino group is illustrated herein. In this procedure, thesubstrate, 167.1, is reacted with a dialkyl 4-aminophenyl phosphonate,171.1, (Epsilon) to give, after deprotection, the imine product, 171.2.The imine forming reaction is conducted in a hydrocarbon solvent such astoluene or xylene, at reflux temperature, in the presence of a basiccatalyst such as sodium methoxide, or an acid catalyst such asp-toluenesulfonic acid, under azeotropic conditions. The product is thenconverted into the 21-chloro 17-(2-furoate) compound, 171.3.

Using the above procedures, but employing, in place of the 4-aminophenylphosphonate, 171.1, different amino-substituted aryl or heteroarylphosphonates, products analogous to 171.3 are obtained.

Example 172

The dienone, 167.1, is reacted with O-(2-aminoethyl)hydroxylamine,172.1, (Pol. J. Chem., 1981, 55, 1163) to yield the oxime, 172.2. Thereaction of steroidal 1,4-dien-3-ones with substituted hydroxylamines isdescribed in J. Steroid Bioch., 4976, 7, 795; the reaction is performedbetween equimolar amounts of the reactants in a polar organic solventsuch as pyridine or methanol, optionally in the presence of acetic acidor sodium acetate. The product is then reacted, in a reductive aminationprocedure, with a dialkyl 4-formylphenyl phosphonate, 172.3, (Epsilon)and sodium triacetoxyborohydride, to yield the amine oxime 172.4. Thepreparation of amines by means of reductive amination procedures isdescribed, for example, in R. C. Larock, Comprehensive OrganicTransformations, 421 (VCH), and in F. A. Carey and R. J. Sundberg,Advanced Organic Chemistry, Part B, 269 (Plenum, 2001). In thisprocedure, the amine component and the aldehyde or ketone component arereacted together in the presence of a reducing agent such as, forexample, borane, sodium cyanoborohydride, sodium triacetoxyborohydrideor diisobutylaluminum hydride, optionally in the presence of a Lewisacid, such as titanium tetraisopropoxide, as described in J. Org. Chem.,1990, 55, 2552.

The amine product, 172.4, is then converted, as described herein, intothe 21-chloro 17-(2-furoate) product, 171.6.

Using the above procedures, but employing, in place of thehydroxylamine, 172.3, different amino-substituted hydroxylamines, and/ordifferent formyl-substituted phosphonates, the products analogous to177.6 are obtained.

Example 173

The BMD-protected dienone, 167.1, is reduced to afford the 1,2-dihydroproduct, 173.1. The catalytic hydrogenation reaction is effected by theuse of tris(triphenylphosphine)rhodium (1) chloride, for example asdescribed in J. Med. Chem., 2001, 44, 602. The product is then reactedwith ethyl formate and a base such as sodium hydride, in an inertsolvent such as toluene or dimethylformamide, as described in J. Am.Chem. Soc., 1964, 86, 1520, to afford the 2-formyl product, 173.2. Thiscompound is then reacted with an alkyl, aralkyl, aryl or heteroarylhydrazine, 173.3, in which the substituent X is either a phosphonategroup or a group which is subsequently transformed into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxyl and the like. The reaction yields theisomeric 2′- and 1′-aryl pyrazoles, 173.4 and 173.5. Thepyrazole-forming reaction is performed between equimolar amounts of thereactants in an acidic solvent such as acetic acid, as described in J.Am. Chem. Soc., 1964, 86, 1520. The pyrazoles, 173.4 and 173.5, are thentransformed, for example by the procedures described herein, via theBMD-protected intermediates, 173.6 and 173.7, into the 21-chloro17-(2-furoate) phosphonates, 173.9 and 173.11.

Example 174

The ketoaldehyde, 173.2, is reacted, as described above, with4-bromo-benzyl hydrazine, 174.1, (Ann., 1968, 717, 104) to give thepyrazoles, 174.2 and 174.3. The 2′-substituted isomer, 174.2, is thencoupled, as described in Example 170, with a dialkyl phosphite, to yieldthe phosphonate, 173.4. The BMD protecting group is then removed and theproduct is converted into the 21-chloro 17-(2-furoate) product, 173.6.

The isomeric pyrazole, 174.3, is subjected to the same series ofreactions to afford the isomeric product, 173.9.

Using the above procedures, but employing different bromo-substitutedhydrazines, the products analogous to 173.6 and 173.9 are obtained.

Example 174

The ketoaldehyde, 173.2, is reacted, as described above, with4-hydroxy-phenyl hydrazine, 174.1, (EP 437105) to produce the pyrazoles,174.2 and 174.3. The 1′-substituted isomer, 174.2, is reacted indimethylformamide at 70° C., with a dialkyl 2-bromoethyl phosphonate,174.4, (Aldrich) and potassium carbonate, to give the ether phosphonate,174.5. The product is then deprotected to afford the triol, 174.6, whichis converted into the 21-chloro 17-(2-furoate) compound, 174.7.

Alternatively, the 2′-substituted pyrazole, 174.3, is coupled, in aMitsonobu reaction, with a dialkyl 2-mercaptoethyl phosphonate, 174.8,(Zh. Obschei. Khim., 1973, 43, 2364) to prepare the thioetherphosphonate, 174.9, which is deprotected, and the product is convertedinto the 21-chloro 17-(2-furoate) analog, 174.11. The preparation ofaromatic ethers and thioethers by means of the Mitsonobu reaction isdescribed, for example, in R. C. Larock, Comprehensive OrganicTransformations, 448 (VCH, 1989), and in F. A. Carey and R. J. Sundberg,Advanced Organic Chemistry, Part B, 153-4 (Plenum, 2001) and in Org.React., 1992, 42, 335. The phenol and the alcohol or thiol component arereacted together in an aprotic solvent such as, for example,tetrahydrofuran, in the presence of a dialkyl azodicarboxylate and atriaryl-phosphine, to afford the ether or thioether products. Theprocedure is also described in Org. React., 1992, 42, 335-656.

Using the above procedures, but employing, in place of the4-hydroxy-phenyl hydrazine, 174.1, different hydroxy-substitutedhydrazines, and/or different dialkyl bromo- or mercapto-substitutedphosphonates, the products analogous to the compounds, 174.7 and 174.11are obtained.

Example 175

The ketoaldehyde, 173.2, is reacted with hydrazine, to afford thepyrazole derivative, 175.1. The reaction of steroidal 2-formyl-3-ketoneswith hydrazine is described in J. Am. Chem. Soc, 1964, 86, 1520. Thereaction is performed in acetic acid at ambient temperature. Thepyrazole product is then reacted with a bromomethyl compound, 175.6, inwhich R² and X are as defined above, or a reactive bromoheteroaromaticreagent, to yield the alkylation products, 175.3 and 175.4. Thealkylation of substituted pyrazoles is described, for example, in T. L.Gilchrist, Heterocyclic Chemistry, 309 (Longman, 1992). The reaction isperformed between equimolar amounts of the substrates in a polar solventsuch as dimethylformamide or tetrahydrofuran, in the presence of a basesuch as dimethylaminopyridine, lithium hexamethyldisilazide and thelike. The products, 175.3 and 175.4, are, except in cases where X isdialkyl-phosphono, converted into the phosphonates, 175.5 and 175.6,using the procedures described herein, anddeprotection/chlorination/acylation then affords the 21-chloro17-(2-furoate) compounds, 175.8 and 175.10.

Example 176

The pyrazole, 175.1, is reacted with 2,5-dibromopyrimidine, 176.1,(Chem. Lett., 1992, 583) to give the pyrazoles, 176.2 and 176.3. Theproducts are then coupled, as described above, with a dialkyl phosphite,to afford after side-chain deprotection and modification, as describedabove, the 21-chloro 17-(2-furoates), 176.5 and 176.7.

Example 177

The pyrazole, 175.1, is reacted in tetrahydrofuran solution, with1,2-bis(bromomethyl)cyclobutane, 177.1 (J. Org. Chem., 1981, 46, 3530)and potassium hexamethyl disilazide, to give the alkylation products,177.1 and 177.2. The 1′-substituted isomer, 177.2, is then reacted, inan Arbuzov reaction, with a trialkyl phosphite to yield, afterdeprotection and side-chain modification, the 21-chloro 17-(2-furoate),177.5. The Arbuzov reaction is described in Handb. OrganophosphorusChem., 1992, 115. In this procedure, in which a bromo substituent isconverted into the corresponding phosphonate, the substrate is heated atfrom about 60° C. to about 160° C. with a five to fifty-fold molarexcess of a trialkyl phosphite, to effect the transformation.

The 2′-substituted pyrazole, 177.3, is subjected to the same series ofreaction to give the amine phosphonate, 177.7.

Using the above procedures, but employing different dibromides, theproducts analogous to 177.5 and 177.7 are obtained.

Example 178

A protection-deprotection sequence in which the 20-ketone group and/orthe 21-hydroxyl group of Budesonide, 178A, are protected to afford thederivative, 178.1. The ketone is protected, for example, by conversionto the cyclic ethylene ketal, by reaction in toluene solution at refluxtemperature with ethylene glycol and an acid catalyst, as described inJ. Am. Chem. Soc., 1955, 77, 1904. Deprotection is effected by reactionwith pyridinium tosylate in aqueous acetone, as described in J. Chem.Soc. Chem. Comm., 1987, 1351.

Alternatively, the 20-ketone is protected by conversion to theN,N-dimethylhydrazone. The dimethyl hydrazone is prepared by thereaction of the ketone, 178A, with N,N-dimethylhydrazine inethanol-acetic acid, as described in Org. Syn., 1970, 50, 102. The groupis removed by treatment with sodium acetate and acetic acid in aqueoustetrahydrofuran, as described in J. Am. Chem. Soc., 1979, 101, 5841.

Alternatively, the 20-ketone is protected as the diethylamine adduct. Inthis procedure, the substrate, 178A, is reacted with titaniumtetrakis(diethylamide), as described in J. Chem. Soc., Chem. Comm.,1983, 406, to afford the adduct. The ketone is deprotected by reactionwith water in an aqueous organic solvent.

The 21-hydroxyl group is protected, for example, by conversion to theacetate ester, by reaction with one molar equivalent of acetyl chloridein dichloromethane/pyridine. The 21-acetoxy group is removed by reactionwith one molar equivalent of lithium hydroxide in aqueousdimethoxyethane.

Alternatively, the 21-hydroxyl group is protected by conversion to thetert. butyl dimethylsilyl ether, by reaction in dimethylformamidesolution with one molar equivalent of tert. butylchlorodimethylsilaneand imidazole, as described in J. Am. Chem. Soc., 1972, 94, 6190. Thesilyl ether is removed by reaction with tetrabutylammonium fluoride intetrahydrofuran solution, as described in J. Am. Chem. Soc., 1972, 94,6190.

The protected compound, 178.1, is then converted into thephosphonate-containing analog, 178.2, using the procedures describedbelow, and the protecting group or groups are then removed, as describedabove, to give the phosphonate, 178.3.

Example 179

The ketone-protected derivative, 179.1, is reacted with an amine orhydroxylamine, 179.2, in which R² is an alkyl, alkenyl, cycloalkyl orcycloalkenyl group, optionally incorporating a heteroatom O, S or N, ora functional group such as an amide, ester, oxime, sulfoxide or sulfoneetc, or an optionally substituted aryl, heteroaryl or aralkyl group,optionally incorporating a heteroatom O, S or N, and X is either aphosphonate group or a group which is subsequently converted into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxy and the like. The reaction is conductedbetween equimolar amounts of the reactants in an aprotic solvent such aspyridine or xylene, or in an alcoholic solvent such as ethanol,optionally in the presence of an acid catalyst, to give the imine oroxime, 179.3. The preparation of oximes of steroidal 3-ketones isdescribed in Anal. Bioch., 1978, 86, 133 and in J. Mass. Spectrom.,1995, 30, 497. The protecting group is then removed, as describedherein, to afford the 20-keto phosphonate product, 179.4.

Example 179A

The preparation of hydroxylamine ethers incorporating a phosphonategroup is also illustrated. In this procedure, a phosphonate, 179.5, inwhich Lv is a leaving group such as bromo or trifluoromethylsulfonyloxy,is reacted with BOC-hydroxylamine, 179.6, (Aldrich) to produce theether, 179.7. The reaction is conducted between equimolar amounts of thereactants in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such as potassium hydroxideor dimethylaminopyridine. Deprotection, for example by treatment withtrifluoroacetic acid, then gives the hydroxylamine ether, 179.8. Theabove procedure is also employed for the preparation of substitutedhydroxylamines which are precursors to phosphonates.

Example 180

The substrate, 179.1, in which the 20-ketone is protected as thedimethyl hydrazone derivative, is reacted with a dialkyl phosphonomethylhydroxylamine, 180.1, prepared as described above from a dialkyltrifluoromethylsulfonyl-oxymethyl phosphonate (Tet. Lett., 1986, 27,1477) and BOC-hydroxylamine, to afford the oxime, 180.2. Deprotection,as described in Example 179, affords the 20-keto phosphonate, 180.3. Theoxime forming reaction is performed at ambient temperature inethanol-acetic acid solution between equimolar amounts of the reactants.

Using the above procedures, but employing, in place of thehydroxyl-amine ether, 180.1, different oxime ethers, 179.2, thecorresponding products, 179.4 are obtained.

Example 181

The preparation of compounds, 179.1, in which the phosphonate group isattached by means of a benzyloxy oxime group is illustrated above. Inthis procedure, the dienone, 179.1, in which the 20-ketone is protectedas the dimethyl hydrazone, is reacted, as described above, withO-(2-bromobenzyl)hydroxylamine, 181.1, prepared as described above from2-bromobenzyl bromide and BOC-protected hydroxylamine, 179.6, to givethe oxime, 181.2. The protecting group is then removed to yield the20-keto product, 181.3. The latter product is then reacted, in thepresence of a palladium catalyst, with a dialkyl phosphite, 181.4, toafford the phosphonate, 181.5. The preparation of arylphosphonates bymeans of a coupling reaction between aryl bromides and dialkylphosphites is described in J. Med. Chem., 1992, 35, 1371. The reactionis performed at ca. 100° in an inert solvent such as toluene, in thepresence of a base such as triethylamine and a catalytic amount oftetrakis(triphenylphosphine)palladium(0).

Alternatively, the bromo compound, 181.3, is coupled with a dialkylvinylphosphonate, 181.6, (Aldrich) to afford the phosphonate, 181.7. Thecoupling of aryl halides with olefins by means of the Heck reaction isdescribed, for example, in Advanced Organic Chemistry, by F. A. Careyand R. J. Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem. Res., 1979,12, 146. The aryl bromide and the olefin are coupled in a polar solventsuch as dimethyl-formamide or dioxan, in the presence of a palladium(0)catalyst such as tetrakis(triphenylphosphine)palladium(0) orpalladium(II) catalyst such as palladium(II) acetate, and optionally inthe presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product, 181.7, isreduced, for example by reaction with diimide, to produce the saturatedanalog, 181.8. The reduction of olefinic bonds is described inComprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p.6ff. The transformation is effected by means of catalytic hydrogenation,for example using a palladium on carbon catalyst and hydrogen or ahydrogen donor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of the bromobenzylreagent, 181.1, different bromo-substituted aryl or heteroaryl alkoxyhydroxylamines, and/or different dialkyl alkenyl phosphonates, theproducts analogous to the compounds, 181.5, 181.7 and 181.8 areobtained.

Example 182

The substrate, 171.1, in which the 20-ketone is protected as thedimethyl-hydrazone, is reacted with a dialkyl 4-aminophenyl phosphonate,182.1, (Epsilon), to give, after deprotection, the imine product, 182.2.The imine forming reaction is conducted in a hydrocarbon solvent such astoluene or xylene, at reflux temperature, in the presence of a basiccatalyst such as sodium methoxide, or an acid catalyst such asp-toluenesulfonic acid, under azeotropic conditions.

Using the above procedures, but employing, in place of the4-amino-phenyl phosphonate, 182.1 different amino-substituted aryl orheteroaryl phosphonates, products analogous to 182.2 are obtained.

Example 183

The preparation of phosphonates in which the phosphonate is attached bymeans of an oximino group and a carbamate linkage is illustrated herein.In this procedure, the dienone, 171.1, in which the 20-ketone isprotected as the dimethylhydrazone, is reacted with 4-aminobutylhydroxylamine, 183.1, (Pol. J. Chem., 1981, 55, 1163) to yield theoxime, 183.2. (The reaction of steroidal 1,4-dien-3-ones withhydroxylamines is described in J. Steroid Bioch., 1976, 7, 795.)

The reaction is performed between equimolar amounts of the reactants ina polar organic solvent such as pyridine or methanol, optionally in thepresence of acetic acid or sodium acetate. The product, 183.2, is thencoupled with a dialkyl 2-hydroxyethyl phosphonate, 183.3, (Epsilon) andcarbonyl diimidazole (CDI), to yield, after deprotection, the carbamateoxime, 183.4. The preparation of carbamates is described inComprehensive Organic Functional Group Transformations, A. R. Katritzky,ed., Pergamon, 1995, Vol. 6, p 416ff, and in Organic Functional GroupPreparations, by S. R. Sandler and W. Karo, Academic Press, 1986, p.260ff. In the procedure, the amine is reacted in an inert aproticsolvent such as dichloromethane or tetrahydrofuran, with phosgene or afunctional equivalent thereof, such as carbonyl diimidazole,triphosgene, pentafluorophenyl carbonate and the like, to afford thecorresponding activated acylamine. The latter compound is then reactedwith an alcohol to yield the carbamate.

Using the above procedures, but employing, in place of theamino-substituted hydrazine, 183.1, different amino-substitutedhydrazines, and/or different hydroxy-substituted phosphonates, theproducts analogous to 183.4 are obtained.

Example 184

The dienone, 178.3, in which the 21-hydroxyl group is protected asdescribed in Example 178 is reduced to afford the 1,2-dihydro product,184.1. The catalytic hydrogenation reaction is effected by the use oftris(triphenyl-phosphine)rhodium (I) chloride, for example as describedin J. Med. Chem., 2001, 44, 602. The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in J. Am. Chem. Soc., 1964,86, 1520, to afford the 2-formyl product, 184.2. This compound is thenreacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine, 184.3, inwhich the substituent X is either a phosphonate group or a group whichis subsequently transformed into a phosphonate-containing substituent.For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl andthe like. The reaction yields, after deprotection of the 21-hydroxylgroup, the isomeric 2′- and 1′-aryl pyrazoles, 184.4 and 184.5. Thepyrazole-forming reaction is performed between equimolar amounts of thereactants in an acidic solvent such as acetic acid, as described in J.Am. Chem. Soc., 1964, 86, 1520. The pyrazoles, 184.4 and 184.5, are thentransformed, for example by the procedures described in Examples 180 and181, into the phosphonates, 184.6 and 184.7.

Example 185

The ketoaldehyde, 184.2, is reacted, as described above, with4-bromophenyl hydrazine, 185.1, (J. Organomet. Chem., 1999, 62, 581) togive the pyrazoles, 185.2 and 185.3. The 2′-substituted isomer 185.2 isthen reacted, as described above, with a dialkyl phosphate, 184.4, togive the phosphonate, 185.5.

The isomeric pyrazole, 185.3, is reacted in a Heck reaction, asdescribed above, with one molar equivalent of a dialkyl 4-vinylphenylphosphonate, 185.6, (Macromolecules, 1998, 31, 2918) to yield thephosphonate, 185.7.

Using the above procedures, but employing different bromo-substitutedhydrazines, and/or different alkenyl-substituted phosphonates, theproducts analogous to 185.5 and 185.7 are obtained.

Example 186

The ketoaldehyde, 184.2, is reacted, as described above, with4-hydroxy-phenyl hydrazine, 186.1, (EP 437105) to produce the pyrazoles,186.2 and 186.3. The 2′-substituted isomer, 186.2, is then reacted indimethylformamide solution at 70° with one molar equivalent of a dialkylbromopropyl phosphonate, 186.4, (J. Amer. Chem. Soc., 2000, 122, 1554)and cesium carbonate, to give the ether phosphonate, 186.5.

Alternatively, the 1′-substituted pyrazole, 186.3, is coupled in aMitsonobu reaction, with a dialkyl 2-mercaptoethyl phosphonate, 186.6,(Zh. Obschei. Khim., 1973, 43, 2364) to prepare the thioetherphosphonate, 186.7. The preparation of aromatic ethers and thioethers bymeans of the Mitsonobu reaction is described, for example, inComprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p.448, and in Advanced Organic Chemistry, Part B, by F. A. Carey and R. J.Sundberg, Plenum, 2001, p. 153-4 and in Org. React., 1992, 42, 335. Thephenol and the alcohol or thiol component are reacted together in anaprotic solvent such as, for example, tetrahydrofuran, in the presenceof a dialkyl azodicarboxylate and a triarylphosphine, to afford theether or thioether products. The procedure is also described in Org.React., 1992, 42, 335-656.

Using the above procedures, but employing, in place of thehydroxyl-phenyl hydrazine, 186.1, different hydroxyaryl hydrazines,and/or different dialkyl bromo- or mercapto-substituted phosphonates,the products analogous to the compounds, 186.5 and 186.7 are obtained.

Example 187

The ketoaldehyde, 184.2, is reacted with hydrazine to afford thepyrazole derivative, 187.1. The reaction of steroidal 2-formyl-3-ketoneswith hydrazine is described in J. Am. Chem. Soc., 1964, 86, 1520. Thereaction is performed in acetic acid at ambient temperature. Thepyrazole product is then reacted with a bromomethyl compound, 187.2, inwhich R² and X are as defined above, or a reactive bromoheteroaromaticreagent, to yield the alkylation products, 187.3 and 187.4. Thealkylation of substituted pyrazoles is described, for example, inHeterocyclic Chemistry, by T. L. Gilchrist, Longman, 1992, p. 309. Thereaction is performed between equimolar amounts of the substrates in apolar solvent such as dimethylformamide or tetrahydrofuran, in thepresence of a base such as dimethylaminopyridine, lithiumhexamethyldisilazide and the like. The products, 187.3 and 187.4, are,except in cases where X is dialkylphosphono, converted into thephosphonates, 187.5 and 187.6, using the procedures described herein.

Example 188

The pyrazole, 187.1, is reacted in dimethylformamide solution at 700with one molar equivalent of a dialkyl 4-bromomethylphenyl phosphonate,188.1, (Tet., 1998, 54, 9341) and lithium hexamethyl disilazide, to givethe pyrazoles, 188.2 and 188.3. Using the above procedures, butemploying different bromomethyl-substituted phosphonates, the productsanalogous to 188.2 and 188.3 are obtained.

Example 189

The pyrazole, 187.1, is reacted in tetrahydrofuran solution with1,3-bis(bromomethyl)cyclopentane, 189.1, (Bull. Soc. Chim. Fr., 1975,1295) and sodium hydride, to give the alkylation products, 189.2 and189.3. The 2′-substituted isomer, 189.2, is then reacted, in a Arbuzovreaction, with a trialkyl phosphite to yield the phosphonate, 189.4. TheArbuzov reaction is described in Handb. Organophosphorus Chem., 1992,115. In this procedure, in which a bromo substituent is converted intothe corresponding phosphonate, the substrate is heated at from about 60°to about 160° with a five to fifty-fold molar excess of a trialkylphosphite, to effect the transformation.

The 2′-substituted pyrazole, 189.3, is reacted at 70° indimethyl-formamide solution with one molar equivalent of a dialkylmethylaminomethyl phosphonate, 189.5, and cesium carbonate, to give theamine phosphonate, 189.6.

Using the above procedures, but employing different dihalides, and/ordifferent amino-substituted phosphonates, the products analogous to189.4 and 189.6 are obtained.

Example 190

A protection-deprotection sequence in which the 20-ketone group ofRimexolone, 190A, is protected to afford the derivative, 190.1. Theketone is protected, for example, by conversion to the cyclic ethyleneketal, by reaction in toluene solution at reflux temperature withethylene glycol and an acid catalyst, as described in J. Am. Chem. Soc.,1955, 77, 1904. Deprotection is effected by reaction with pyridiniumtosylate in aqueous acetone, as described in J. Chem. Soc., Chem. Comm.,1987, 1351.

Alternatively, the 20-ketone is protected by conversion to theN,N-dimethylhydrazone. The dimethyl hydrazone is prepared by thereaction of the ketone, 190A, with N,N-dimethylhydrazine inethanol-acetic acid, as described in Org. Syn., 1970, 50, 102. The groupis removed by treatment with sodium acetate and acetic acid in aqueoustetrahydrofuran, as described in J. Am. Chem. Soc., 1979, 101, 5841.

Alternatively, the 20-ketone is protected as the diethylamine adduct. Inthis procedure, the substrate, 190.1, is reacted with titaniumtetrakis-(diethylamide), as described in J. Chem. Soc., Chem. Comm.,1983, 406, to afford the adduct. The ketone is deprotected by reactionwith water in an aqueous organic solvent.

The protected compound, 190.2, is then converted into thephosphonate-containing analog, 190.3, using the procedures describedbelow, and the protecting group or groups are then removed, as describedabove, to give the phosphonate, 190.3.

Example 191

The ketone-protected derivative, 190.1, is reacted with an amine orhydroxylamine, 191.1, in which R² is an alkyl, alkenyl, cycloalkyl orcycloalkenyl group, optionally incorporating a heteroatom O, S or N, ora functional group such as an amide, ester, oxime, sulfoxide or sulfoneetc, or an optionally substituted aryl, heteroaryl or aralkyl group,optionally incorporating a heteroatom O, S or N, and X is either aphosphonate group or a group which is subsequently converted into aphosphonate-containing substituent. For example, X is dialkylphosphono,bromo, hydroxy, amino, carboxy and the like. The reaction is conductedbetween equimolar amounts of the reactants in an aprotic solvent such aspyridine or xylene, or in an alcoholic solvent such as ethanol,optionally in the presence of an acid catalyst, to give the imine oroxime, 191.2. The preparation of oximes of steroidal 3-ketones isdescribed in Anal. Bioch., 1978, 86, 133 and in J. Mass. Spectrom.,1995, 30, 497. The protecting group is then removed, as described inExample 190, to afford the 20-keto phosphonate product, 191.3.

Example 191A

The preparation of hydroxylamine ethers incorporating a phosphonategroup is also illustrated. In this procedure, a phosphonate, 191.4, inwhich Lv is a leaving group such as bromo or trifluoromethylsulfonyloxy,is reacted with BOC-hydroxylamine, 191.5, (Aldrich) to produce theether, 191.6. The reaction is conducted between equimolar amounts of thereactants in a polar solvent such as dimethylformamide ortetrahydrofuran, in the presence of a base such as potassium hydroxideor dimethylaminopyridine. Deprotection, for example by treatment withtrifluoroacetic acid, then gives the hydroxylamine ether, 191.7. Theabove procedure is also employed for the preparation of substitutedhydroxylamines which are precursors to phosphonates.

Example 192

The substrate, 190.1, in which the 20-ketone is protected as thedimethyl hydrazone derivative, is reacted with a dialkyl phosphonomethylhydroxylamine, 192.1, prepared as described above from a dialkyltrifluoromethyl-sulfonyl-oxymethyl phosphonate (Tet. Lett., 1986, 27,1477) and BOC-hydroxylamine, to afford the oxime, 192.2. Deprotection,as described in Example 191, then affords the 20-keto phosphonate,192.3. The oxime forming reaction is performed at ambient temperature inethanol-acetic acid solution between equimolar amounts of the reactants.

Using the above procedures, but employing, in place of thehydroxyl-amine ether, 192.1, different oxime ethers, 191.1, thecorresponding products, 191.3 are obtained.

Example 193

The dienone, 190.1, in which the 20-ketone is protected as the dimethylhydrazone, is reacted, as described above, withO-(3-bromobenzyl)hydroxyl-amine, 193.1, prepared as described above from3-bromobenzyl bromide and BOC-protected hydroxylamine, 191.5, to givethe oxime, 193.2. The protecting group is then removed to yield the20-keto product 193.3. The latter product is then reacted, in thepresence of a palladium catalyst, with a dialkyl phosphate, 193.4, toafford the phosphonate, 193.5. The preparation of arylphosphonates bymeans of a coupling reaction between aryl bromides and dialkylphosphites is described in J. Med. Chem., 1992, 35, 1371. The reactionis performed at ca. 100° C. in an inert solvent such as toluene, in thepresence of a base such as triethylamine and a catalytic amount oftetrakis(triphenylphosphine)-palladium(0).

Alternatively, the bromo compound, 193.3, is coupled with a dialkylpropenylphosphonate, 193.6, (Aldrich) to afford the phosphonate, 193.7.The coupling of aryl halides with olefins by means of the Heck reactionis described, for example, in F. A. Carey and R. J. Sundberg, AdvancedOrganic Chemistry, 503ff (Plenum, 2001) and in Acc. Chem. Res., 1979,12, 146. The aryl bromide and the olefin are coupled in a polar solventsuch as dimethylformamide or dioxan, in the presence of a palladium(0)catalyst such as tetrakis(triphenyl-phosphine)palladium(0) orpalladium(II) catalyst such as palladium(II) acetate, and optionally inthe presence of a base such as triethylamine or potassium carbonate.Optionally, the styrenoid double bond present in the product, 193.7, isreduced, for example by reaction with diimide, to produce the saturatedanalog, 193.8. The reduction of olefinic bonds is described in R. C.Larock, Comprehensive Organic Transformations, 6ff (VCH, 1989). Thetransformation is effected by means of catalytic hydrogenation, forexample using a palladium on carbon catalyst and hydrogen or a hydrogendonor, or by the use of diimide or diborane.

Using the above procedures, but employing, in place of the bromobenzylreagent, 193.1, different bromo-substituted aryl or heteroaryl alkoxyhydroxyl-amines, and/or different dialkyl alkenyl phosphonates, theproducts analogous to the compounds, 193.5, 193.7 and 193.8 areobtained.

Example 194

The substrate, 190.1, in which the 20-ketone is protected as thedimethylhydrazone, is reacted with a dialkyl 4-amino-2-furylphosphonate, 194.1, prepared by the palladium catalyzed couplingreaction, as described above, between 4-amino-2-bromofuran (Tet., 1987,43, 3295) and a dialkyl phosphite, to give, after deprotection, theimine product, 194.2. The imine forming reaction is conducted in ahydrocarbon solvent such as toluene or xylene, at reflux temperature, inthe presence of a basic catalyst such as sodium methoxide, or an acidcatalyst such as p-toluenesulfonic acid, under azeotropic conditions.

Using the above procedures, but employing, in place of the 4-aminofurylphosphonate, 194.1, different amino-substituted aryl or heteroarylphosphonates, products analogous to 194.2 are obtained.

Example 195

The dienone, 190.1, in which the 20-ketone is protected as thedimethylhydrazone, is reacted with 2-carboxyethyl hydroxylamine, 195.1,(J. Med. Chem., 1990, 33, 1423) to yield the oxime, 195.2. The reactionof steroidal 1,4-dien-3-ones with hydroxylamines is described in J.Steroid Bioch., 1976, 7, 795; the reaction is performed betweenequimolar amounts of the reactants in a polar organic solvent such aspyridine or methanol, optionally in the presence of acetic acid orsodium acetate. The product, 195.2, is then coupled with a dialkyl4-aminophenyl phosphonate, 195.3, (Epsilon) and dicyclohexylcarbodiimide, to yield, after deprotection, the amide oxime, 195.4. Thepreparation of amides from carboxylic acids and derivatives isdescribed, for example, in S. R. Sandier and W. Karo, Organic FunctionalGroup Preparations, 274 (Academic Press, 1968), and R. C. Larock,Comprehensive Organic Transformations, 972ff (VCH, 1989). The carboxylicacid is reacted with the amine in the presence of an activating agent,such as, for example, dicyclohexylcarbodiimide ordiisopropylcarbodiimide, optionally in the presence of, for example,hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxypyridone, in anon-protic solvent such as, for example, pyridine, DMF ordichloromethane, to afford the amide.

Alternatively, the carboxylic acid may first be converted into anactivated derivative such as the acid chloride, anhydride, mixedanhydride, imidazolide and the like, and then reacted with the amine, inthe presence of an organic base such as, for example, pyridine, toafford the amide.

The conversion of a carboxylic acid into the corresponding acid chloridecan be effected by treatment of the carboxylic acid with a reagent suchas, for example, thionyl chloride or oxalyl chloride in an inert organicsolvent such as dichloromethane, optionally in the presence of acatalytic amount of dimethylformamide.

Using the above procedures, but employing, in place of thecarboxy-substituted hydroxylamine, 195.1, different carboxy-substitutedhydroxylamines, and/or different amino-substituted phosphonates, theproducts analogous to 195.4 are obtained.

Example 196

The dienone, 190A, is reduced to afford the 1,2-dihydro product, 196.1.The catalytic hydrogenation reaction is effected by the use oftris(triphenyl-phosphine)rhodium (I) chloride, for example as describedin J. Med. Chem., 2001, 44:, 602. The product is then reacted with ethylformate and a base such as sodium hydride, in an inert solvent such astoluene or dimethylformamide, as described in J. Am. Chem. Soc., 1964,86, 1520, to afford the 2-formyl product, 196.2. This compound is thenreacted with an alkyl, aralkyl, aryl or heteroaryl hydrazine, 196.3, inwhich the substituent X is either a phosphonate group or a group whichis subsequently transformed into a phosphonate-containing substituent.For example, X is dialkylphosphono, bromo, hydroxy, amino, carboxyl andthe like. The reaction yields the isomeric 2′- and 1′-aryl pyrazoles,196.4 and 196.5. The pyrazole-forming reaction is performed betweenequimolar amounts of the reactants in an acidic solvent such as aceticacid, as described in J. Am. Chem. Soc., 1964, 86, 1520. The pyrazoles,196.4 and 196.5, are then transformed, for example, by the proceduresdescribed in Examples 192 and 193, into the phosphonates, 196.6 and196.7. Optionally, the reduction and formylation reactions are performedon the substrate, 190.1, in which the 20-ketone is protected as thecyclic ethylene ketal.

Example 197

The ketoaldehyde, 196.2, is reacted, as described above, with3-hydroxy-phenyl hydrazine, 197.1, (JP 03011081) to give the pyrazoles,197.2 and 197.3. The 2′-substituted isomer, 197.2, is then reacted indimethylformamide solution at 70° with one molar equivalent of a dialkyl2-bromoethyl phosphonate, 197.4, (Aldrich) and potassium carbonate, togive the ethoxy phosphonate, 197.5.

The isomeric pyrazole, 197.3, is reacted in a Mitsonobu with one molarequivalent of a dialkyl 3-hydroxypropyl phosphonate, 197.6, (Zh.Obschei. Khim., 1974, 44, 1834) to yield the phosphonate, 197.7. Thepreparation of aromatic ethers by means of the Mitsonobu reaction isdescribed, for example, in R. C. Larock, Comprehensive OrganicTransformations, 448 (VCH, 1989), and in F. A. Carey and R. J. Sundberg,Advanced Organic Chemistry, Part B, 153-4 (Plenum, 2001) and in Org.React., 1992, 42, 335. The phenol and the alcohol or thiol component arereacted together in an aprotic solvent such as, for example,tetrahydrofuran, in the presence of a dialkyl azodicarboxylate and atriarylphosphine, to afford the ether or thioether products. Theprocedure is also described in Org. React., 1992, 42, 335-656.

Using the above procedures, but employing different hydroxy-substitutedhydrazines, and/or different bromo or hydroxy-substituted phosphonates,the products analogous to 195.5 and 197.6 are obtained.

Example 198

The ketoaldehyde, 196.2, is reacted, as described above, with4-amino-phenyl hydrazine, 198.1, (Syn. Comm., 1974, 4, 57) to producethe pyrazoles, 198.2 and 198.3. The 2′-substituted isomer, 198.2, isthen reacted in dimethylformamide solution at 70° with one molarequivalent of a dialkyl 3-bromopropyl phosphonate, 198.4, (J. Amer.Chem. Soc., 2000, 122, 1554) and cesium carbonate, to give the aminephosphonate, 198.5.

Alternatively, the 1′-substituted pyrazole, 198.3, is coupled with adialkyl 4-hydroxymethylphenyl phosphonate, 198.6, (U.S. Pat. No.5,569,664) and carbonyl diimidazole to prepare the carbamatephosphonate, 198.7. The preparation of carbamates is described inComprehensive Organic Functional Group Transformations, A. R. Katritzky,ed., Pergamon, 1995, Vol. 6, p 416ff, and in Organic Functional GroupPreparations, by S. R. Sandler and W. Karo, Academic Press, 1986, p.260ff. In the procedure, the amine is reacted in an inert aproticsolvent such as dichloromethane or tetrahydrofuran, with phosgene or afunctional equivalent thereof, such as carbonyl diimidazole,triphosgene, pentafluorophenyl carbonate and the like, to afford thecorresponding activated acylamine. The latter compound is then reactedwith an alcohol to yield the carbamate.

Using the above procedures, but employing, in place of the aminophenylhydrazine, 198.1, different amino-substituted hydrazines, and/ordifferent dialkyl bromo or hydroxy-substituted phosphonates, theproducts analogous to the compounds, 198.5 and 198.7 are obtained.

Example 199

The ketoaldehyde, 196.2, is reacted with hydrazine to afford thepyrazole derivative, 199.1. The reaction of steroidal 2-formyl-3-ketoneswith hydrazine is described in J. Am. Chem. Soc., 1964, 86, 1520. Thereaction is performed in acetic acid at ambient temperature. Thepyrazole product is then reacted with a bromomethyl compound, 199.2, inwhich R² and X are as defined above, or a reactive bromoheteroaromaticreagent, to yield the alkylation products, 199.3 and 199.4. Thealkylation of substituted pyrazoles is described, for example, inHeterocyclic Chemistry, by T. L. Gilchrist, Longman, 1992, p. 309. Thereaction is performed between equimolar amounts of the substrates in apolar solvent such as dimethylformamide or tetrahydrofuran, in thepresence of a base such as dimethylaminopyridine, lithiumhexamethyldisilazide and the like. The products, 199.3 and 199.4, are,except in cases where X is dialkylphosphono, converted into thephosphonates, 199.5 and 199.6, using the procedures described herein.

Example 200

The pyrazole, 199.1, is reacted in dimethylformamide solution at 70° C.with one molar equivalent of a dialkyl 4-bromobutenyl phosphonate,200.1, (J. Med. Chem., 1992, 35, 1371) and lithium hexamethyldisilazide, to give the pyrazoles, 200.2 and 200.3.

Using the above procedures, but employing different bromo-substitutedphosphonates, the products analogous to 200.2 and 200.3 are obtained.

Example 201

The pyrazole, 199.1, is reacted in tetrahydrofuran solution with2,5-bis(bromomethyl)furan, 201.1, (Tet., 1999, 55, 4709) and potassiumhexamethyl disilazide, to give the alkylation products, 201.2 and 201.3.The 2′-substituted isomer, 201.2, is then reacted, in a Arbuzovreaction, with a trialkyl phosphite to yield the phosphonate, 201.4. TheArbuzov reaction is described in Handb. Organophosphorus Chem., 1992,115. In this procedure, in which a bromo substituent is converted intothe corresponding phosphonate, the substrate is heated at from about 60°to about 160° with a five to fifty-fold molar excess of a trialkylphosphite, to effect the transformation.

The 1′-substituted pyrazole, 201.3, is reacted at ambient temperature indimethylformamide solution with one molar equivalent of a dialkylmercapto-methyl phosphonate, 201.5, (J. Med. Chem., 1985, 26, 1688) andcesium carbonate, to give the thioether phosphonate, 201.6.

Using the above procedures, but employing different dihalides, and/ordifferent mercapto-substituted phosphonates, the products analogous to201.4 and 201.6 are obtained.

Example 202

Derivatives of the C-21 primary hydroxy group of the type, 202.1, arereadily prepared by alkylating triamcinolone acetonide, 202A, with theappropriate phosphonate as shown.

Example 203

After chemoselective extraction of the primary hydroxy proton ofcompound, 202A, using one equivalent of sodium hydride, the phosphonatetriflate is added to provide the ether, 203.1.

Example 204

The primary hydroxy group is masked by an appropriate protecting group.After alkylation at the secondary hydroxy moiety of, 204.1, with aleaving group-attached phosphonate and subsequent deprotection, desiredanalog, 204.2, is obtained.

Example 205

Triamcinolone acetonide, 202A, is chemoselectively protected as itssilyl ether using the standard TBSCl and imidazole conditions (J. Am.Chem. Soc. 1972, 94, 6190). Alkylation at the exposed secondary hydroxygroup with sodium hydride and the phosphonate triflate furnishes theintermediate, 205.6. Final TBAF deprotection of the silyl ether affordsthe desired product, 205.7.

Example 206

Phosphonate derivatives of the acetal are readily prepared from acidichydrolysis of triamcinolone acetonide, 202A, to the diol, 206.1, asillustrated in Scheme 3.1. Acetylization of the diol with a phosphonatealdehyde furnishes the desired acetal, 206.2.

Example 207

Triamcinolone acetonide, 202A, is first hydrolized in aqueous aceticacid. (Can. J. Chem. 1983, 61, 634) The resulting diol, 207.1, isacetalized with the phosphonate aldehyde and perchloric acid, affordingthe acetal, 207.2 (J. Med. Chem. 1996, 39, 4888-4896).

Example 208

Derivatization at the C-11 hydroxy group is accomplished throughalkylation of rimexolone, 208A, with the appropriate phosphonate,furnishing analogs of the type, 208.1.

After sodium hydride extraction of the hydroxy proton in, 208A, diethylphosphonate triflate is added to afford ether, 208.2.

Example 209

Derivatives of the carbonyl at C-17 are readily prepared fromsaponification of fluticasone, 209A, to the carboxylic acid, 209.1.Activation of the carboxylic acid, followed by reaction withthiophosphonate or aminophosphonate nucleophile furnishes the desiredthioester, 209.2, and amide, 209.3, respectively.

Example 210

Fluticasone, 209A, is first saponified with potassium hydroxide inacetone. (Synthesis, 2002, 921-927) The resulting carboxylic acid,209.1, is activated to the carboxylic acid imidazole by the addition of1,1′-carbonyldiimidazole (CDI) (J. Med. Chem. 1994, 37, 3717-3729).Treatment with the thiophosphonate affords thioester, 210.1. Magnesiumethoxide may be added to help enhance the reactivity (Tetrahedron Lett.1981, 22, 3245-3246). Alternatively, the carboimidazole intermediatederived from, 209.1, can be reacted with the aminophosphonate to produceamide, 210.2.

Example 211

The less sterically hindered C-11 hydroxy group is selectively alkylatedwith the appropriate phosphonate to give analogs of formula, 211.1.

Example 212

After regioselective extraction of the C-11 hydroxy proton in, 209A,using one equivalent of sodium hydride, the phosphonate triflate isadded to provide the ether, 212.1.

Example 213

The C-11 hydroxy group is masked by an appropriate protecting group.After alkylation at the C-17 hydroxy moiety of, 213.1, with a leavinggroup-attached phosphonate and subsequent deprotection, desired analog,213.3, is obtained.

Example 214

Fluticasone 209A is regioselectively protected as its C-11 acetate esterusing the standard acetic anhydride and DMAP conditions (J. Org. Chem.1998, 63, 2342-2347). Alkylation at the exposed C-17 hydroxy group withsodium hydride and the phosphonate triflate furnishes the intermediate,214.2. Final ammonia deprotection of the acetate affords the desiredether, 214.3.

Example 215

Derivatization at the C-11 hydroxy group is accomplished throughalkylation of mometasone fuorate, 215A, with the appropriatephosphonate, furnishing analogs of the type, 215.1.

Example 216

After sodium hydride extraction of the hydroxy proton in 215A, diethylphosphonate triflate is added to afford ether, 216.1.

Example 217

Following protection of the only exposed hydroxy group in mometasonefuorate, 215A, intermediate, 217.1, is saponified to give alcohol,217.3. Alkylation at the C-17 hydroxy group with the appropriatephosphonate and subsequent deprotection provides the desired product,217.4.

Example 218

Mometasone fuorate, 215A, is protected as its silyl ether using thestandard TBSCl and imidazole conditions (J. Am. Chem. Soc., 1972, 94,6190). Saponification of the fuoryl ester moiety using aqueous sodiumhydroxide provides the alcohol, 218.1 (J. Chem. Soc. Perkin Trans. 1,1993, 12, 1359-1366). The tertiary hydroxy group is alkylated by theaddition of sodium hydroxide and the phosphonate triflate. Afterdeprotection of the silyl ether in intermediate, 218.3, with TBAF,diethyl phosphonate, 218.4, results.

Example 219

Derivatization at the C-11 hydroxy group is accomplished throughalkylation of methylprednisolone aceponate (219A) with the appropriatephosphonate, furnishing analogs of Example 219.1.

Example 220

After sodium hydride extraction of the hydroxy proton in 219A, diethylphosphonate triflate is added to afford ether, 220.1.

Example 221

Following protection of the only exposed hydroxy group in 219A,intermediate, 221.1, is saponified to give diol, 221.2. Alkylation atthe primary hydroxy group with the appropriate phosphonate andsubsequent acylation provides the propionate ester, 221.4. The desiredproduct, 221.5, is achieved after deprotection.

Example 222

Methylprednisolone aceponate, 219A, is protected as its silyl etherusing the standard TBSCl and imidazole conditions (J. Am. Chem. Soc.,1972, 94, 6190). Saponification of both ester moieties using aqueoussodium hydroxide provides the diol, 222.2. The less sterically hinderedprimary hydroxy group is alkylated by the addition of sodium hydroxideand the phosphonate triflate. After treating intermediate, 222.3, withpropionic anhydride in pyridine, the previously hydrolized C-17propionic ester is replaced (J. Med. Chem., 1980, 23, 430-437). TBAFdeprotection of the silyl ether furnishes diethyl phosphonate, 222.5.

Example 223

The two hydroxy groups of diol, 221.2, are regioselectivelydifferentiated by protection at the primary site, thus allowingalkylation at the tertiary hydroxy group. The resulting phosphonateintermediate, 223.1, is then deprotected to afford the diol, 223.3.Again the more accessible primary hydroxy group is acylated to producethe desired analog, 223.4.

Example 224

Diol, 222.2, is alkylated with the diethyl phosphonate triflate, theresulting intermediate, 224.2, is treated with TBAF to give diol, 224.3.Acetic anhydride and pyridine are used to generate the final product,224.4 (J. Mol. Biol., 1972, 72, 219).

Example 225

Compounds such as, 225.1, can be made according to the general routeoutlined below.

Example 226

PNP-405, 225A, is prepared according to the method of Littler, B. J. etal., 7^(th) International Conference on Organic Process Research andDevelopment, New Orleans, La., Mar. 16-19, 2003. PNP-405 is treated in asolvent such as tetrahydrofuran or dimethylformamide with a base such assodium hydride. When bubbling ceases, diethyl phosphonomethyltriflate(prepared according to Tetrahedron Lett., 1986, 27, 1477) is added, toprovide compound, 226.1, as the desired product.

Example 227

Compounds such as 227.1 (where X═O, Z=CH₂OH), can be prepared accordingto the procedure of Littler, B. J. et al., 7^(th) InternationalConference on Organic Process Research and Development, New Orleans,La., Mar. 16-19, 2003 (Schemes 3 and 4). The starting material,2-benzyloxyphenylacetic acid, 227.1, (provided by Avocado) can beacylated via the mixed anhydride with the oxazolidinone shown at 80-85°C., with triethylamine as base to provide compound, 227.2. Alow-temperature alkylation with bromoacetonitrile results in theformation of compound, 227.3, with good diastereomeric ratio. Removal ofthe chiral auxiliary under reductive conditions yields compound, 227.4,without racemization. Protection of the resulting alcohol with thetrityl group provides compound, 227.5. Subsequent pyrrole ringconstruction as well as cyclo-guanidinylation reaction to prepare thesix-membered 2-aminopyrimidone ring is performed as described in Example228 for compound, 228.9, to provide compound, 227.6.

Example 228

Compound, 228.1, (where X═O, Z=H) can be prepared according to thegeneral route outlined above. The starting material,3-(2-benzyloxy-phenyl)-propionitrile, 228.1, is available by Lewisacid-mediated reaction of phenol with acrylonitrile according to U.S.Pat. No. 2,789,995, published in 1954. Intermediate, 227.5, can followthe same synthetic steps as outlined here to provide compound, 227.1.

Pyrrole ring construction can be completed in three steps from3-(2-benzyloxy-phenyl)-propionitrile, 228.1. Formation of3-hydroxy-acrylonitrile, 228.2, can be achieved by exposure of, 228.1,to LDA and ethyl formate. Condensation of this product with2-Amino-malonic acid diethyl ester in EtOH and sodium acetate yieldscompound, 228.3, which undergoes a decarboxylative cyclization in thebasic medium of NaOH and EtOH to provide pyrrole, 228.4. In case ofcompound, 227.1, synthesis, the trityl protecting group on the benzylicalcohol is removed at this stage. Subsequently, guanidinylation reactionusing cyanamide provides compound, 228.5, which, upon treatment withsodium hydroxide, cyclizes to form the 2-aminopyrimidone ring (compound,228.6). Removal of the phenolic protecting group under hydrogenolysisconditions provides the free phenol, which is used as the attachmentsite for the pro-drug group. A variety of linkers may be utilized toattach the pro-drug moiety to the backbone molecule. A particularexample in which diethyl phosphono-methyltriflate is used as thestarting materials is shown is above. Therefore, compound, 228.7, istreated in a solvent such as tetrahydrofuran or dimethylformamide with abase such as sodium hydride or cesium carbonate. When bubbling ceases,diethyl phosphonomethyltriflate (prepared according to TetrahedronLett., 1986, 27, 1477) is added, to provide compound, 228.2, as thedesired product.

Example 229

Compounds such as, 229.1, (where X═O, Y═H, Z=CH₂OH) can be prepared from4-benzyloxyphenylacetic acid (available from Aldrich). Following asimilar sequence to that demonstrated above, intermediate, 229.5, can beprepared. Proceeding with the sequence shown above, 229.5, can betransformed to the desired product, 229.1.

Compounds such as, 230A, can be made according to the general routeoutlined above.

Example 231

Preparation of DADMe-ImmG is reported in Lewandowics A. et al.,Biochemistry, 2003, 42, 6057. The tertiary nitrogen of the ring may notinterfere with the alkylation of the secondary alcohol and in that casedoes not need to be protected, although standard protection anddeprotection protocols as described in Greene, T., Protective Groups inOrganic Synthesis, Wiley-Interscience, 1999 may be used if necessary.Reaction of the primary alcohol, 231.1, with base followed by additionof the appropriately activated phosphonate yields the protected product.Global deprotection yields the desired phosphonate, 231.2.

Example 232

Compounds such as, 232.1, can be made according to the general routeoutlined above.

Example 233

The protected DADMe derivative can be treated with treated in a solventsuch as tetrahydrofuran or dimethylformamide with a base such as sodiumhydride. When bubbling ceases, diethyl phosphonoethylltriflate (preparedaccording to Tetrahedron Lett., 1986, 27, 1477) is added, yielding thedesired phosphonate ester. Removal of the protecting group can beperformed as described in Greene, T., Protective Groups in OrganicSynthesis, Wiley-Interscience, 1999 to provide the desired phosphonateester, 233.1.

Example 234

Compounds such as, 234.2, can be made according to the general routeoutlined above.

CP-690,550,3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile,234.1, can be prepared as described in WO 02096909 and WO 03048162.Enolate formation at the α-cyanoamide position using over 2 equivalentsof base followed by addition of diethyl phosphonomethyltriflate(prepared according to Tetrahedron Lett., 1986, 27, 1477) yields thedesired compound, 234.3. A solvent such as THF, DMF or other anhydroussolvents may be used for this reaction. In case the pyrrole nitrogeninterferes with the desired alkylation, a protecting group such as BOCmay be introduced before the alkylation reaction. Removal of the BOCgroup can be accomplished by exposure of the reaction product to TFA asdescribed in Greene, T., Protective groups in Organic Synthesis,Wiley-Interscience, 1999.

Example 235

Compound, 235.1, is prepared according to WO 02096909. Protection of thepyrrole nitrogen using a tosyl group is achieved as described inSakamoto, T. et al., Tetrahedron Lett. 1994, 35, 18, 2919. Ortholithiation using t-BuLi and quenching with formaldehyde as described inthe above reference as well as Seela, F. et al., Chem. Ber. 1977, 110,4, 1462 introduces a substituent at the requisite site. The primaryalcohol so formed may be used for attachment of the phosphonate moietyvia ether formation using base and diethyl phosphono-methyltriflate(prepared according to Tetrahedron Lett., 1986, 27, 1477) in ananhydrous solvent. Removal of the benzyl protecting group is achievedusing hydrogenolysis conditions. The piperidine nitrogen is then coupledwith cyano-acetic acid 2,5-dioxo-pyrrolidine-1-yl ester to providecompound, 235.5. Removal of the tosyl protecting group can be achievedusing basic conditions to provide the desired product, 235.6.

Example 236

Specifically,(1-benzyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine,compound, 236.1, (prepared as described in WO 02,096,909) is firstprotected on the pyrrole nitrogen using a tosyl group. Subsequentformylation using the procedure reported by Sakamoto, T. et al.,(Tetrahedron Lett. 1994, 35, 2919) provides compound, 236.3. The primaryalcohol is then treated in a solvent such as tetrahydrofuran ordimethyl-formamide with a base such as sodium hydride. When bubblingceases, diethyl phosphonomethyltriflate (prepared according toTetrahedron Lett., 1986, 27, 1477) is added, yielding the desiredproduct, 236.4. Debenzylation of the piperidine nitrogen following bycoupling to cyano-acetic acid 2,5-dioxo-pyrrolidine-1-yl ester givescompound, 236.5. Removal of the tosyl protecting group provides thedesired pro-drug, 236.6.

Example 237

The syntheses of phosphonate compounds of the invention and ofintermediate compounds necessary for their synthesis are illustratedherein.

Example 238

The preparation of phosphonates of phosphonate compounds of theinvention is illustrated above. The5-hydroxy-1-β-D-ribofuranosyl-1H-imidazole-4-carboxamide, 238.1(prepared according to U.S. Pat. No. 3,888,843), can be treated in asolvent such as tetrahydrofuran or dimethyl-formamide with a base suchas sodium hydride. When bubbling ceases, diethyl phosphonomethyltriflate(prepared according to Tetrahedron Lett., 1986, 27, 1477) is added,yielding the desired phosphonate diester 238.2.

Example 239

The preparation of the phosphonate esters is illustrated above. Compound239.1,5-hydroxy-1-(4-hydroxy-5-hydroxymethyl-tetrahydro-furan-2-ylmethyl)-1H-imidazole-4-carboxylicacid amide, prepared by addition of the imidazole base (JP Kokai 7688965) onto the 3,5-bis-protected 2-deoxy-D-erythro-pentofuranosylchloride (Hayashi, M. et al., Chem. Pharm. Bull., 1975, 23, 1, 245;Montgomery, J. A. et al., J. Med. Chem., 1969, 12, 3, 498; and Iwamoto,R. H. et al., J. Med. Chem., 1963, 6, 684), is protected on theimidazol-4-ol. Oxidation of the 5′-OH followed by elimination providesglycal, 239.2. (See the procedure in Zemlicka J. et al., J. Am. Chem.Soc., 1972, 94, 9, 3213.) Selenoetherification provides the protectedphosphonate, 239.3 (Kim, C. et al., J. Org. Chem., 1991, 56, 2642).Oxidative elimination of the phenylselenide (as described in Kim, C. etal., J. Org. Chem., 1991, 56, 2642) followed by stereoselectivedihydroxylation provides the diol 239.4. Finally, the protecting groupis removed to provide compound 239.5.

Example 240

The preparation of the phosphonatesis illustrated above. Specifically,compound 239.1,5-hydroxy-1-(4-hydroxy-5-hydroxymethyl-tetrahydrofuran-2-ylmethyl)-1H-imidazole-4-carboxylicacid amide, is first protected using a TBS group. Subsequent oxidationwith PtO₂ proceeds to provide carboxylic acid 240.1. Decarboxylativeelimination is achieved using dimethylformamide dineopentyl acetal inDMF at high temperature (Zemlicka J. et al., J. Am. Chem. Soc., 1972,94, 9, 3213). Once the furanoid glycal 240.2 is in hand, it is treatedwith silver perchlorate in the presence ofdiethyl(hydroxylmethyl)phosphonate (Phillion, D. et al., TetrahedronLett., 1986, 27, 1477) to provide the phosphonate 240.3 (Kim, C. et al.,J. Org. Chem., 1991, 56, 2642). Oxidative elimination of the selenidefollowed by dihydroxylation using osmium tetraoxide provides a diol,240.5, with the desired stereochemistry. Deprotection of the TBS groupcan be achieved using TBAF to provide compound 240.6.

Example 241

The synthesis of compounds of the invention that are analogs of CsA,241A, (and related cyclosporins) are shown herein.

Example 242

The syntheses of phosphonate compounds of the invention and ofintermediate compounds necessary for their synthesis are illustratedherein. The olefin metathesis methodology is described in J. Med. Chem.,2003, 46, 674.

Example 243

The preparation of compounds of the invention having phosphonate groupsand intermediate compounds useful for their synthesis are illustratedherein.

Example 244

The preparation of compounds of the invention having phosphonate groupsand intermediate compounds useful for their synthesis are illustratedherein.

Example 245

The conversion of various substituents into the group link-P(O)(OR¹)₂,where R¹ is as defined above, or indeed the final stage of P(O)RR^(o),as defined above, can be effected at any convenient stage of thesynthetic sequence, or in the final step. The selection of anappropriate step for the introduction of the phosphonate substituent ismade after consideration of the chemical procedures required and thestability of the substrates to those procedures. It may be necessary toprotect reactive groups, for example hydroxyl, amino, during theintroduction of the group link-P(O)(OR¹)₂ or P(O)RR^(o). Specificexamples of compounds of the invention having formulae, 245.5-245.8, areshown herein.

The compounds of the invention are synthesized according to the methodsdescribed herein. Exemplary intermediate phosphonate esters are shown,wherein R¹ is hydrogen, alkyl, aryl, haloalkyl, alkenyl, aralkyl, oraryl. These compounds can be used to prepare the compounds of theinvention, such as those illustrated herein, by one skilled in the art,using known methods for synthesis of substituted phosphonates. Thesemethods are similar to those described for the synthesis of amides. Thepreparation of amides from carboxylic acids and derivatives isdescribed, for example, in “Organic Functional Group Preparations,” byS. R. Sandler and W. Karo, Academic Press, 1968, p. 274. Further methodsdescribed in the following Examples for the synthesis of the phosphonatediesters and can in some cases be applied to the synthesis ofphosphoramides.

The phosphonate esters, 245.1-245.4, for conversion into the phosphonatemoieties bearing an amino acid, or a lactate esters are shown in herein.Cyclosporin A (CsA) 245.10, can be purchased from Sigma Aldrich,synthesized (See U.S. Pat. No. 4,396,542) or obtained from biologicalsources as described in U.S. Pat. No. 4,117,118. Other cyclosporinderivatives can be either synthetic in nature (See U.S. Pat. No.4,396,542) or isolated by similar means to CsA (See U.S. Pat. No.6,410,696 B1).

The preparation of the phosphonate linkage to CsA through the hydroxylgroup of amino acid 1 to give compounds of formula 245.1 is illustratedherein. CsA, 245.10, is dissolved in a suitable solvent such as, forexample, DMF or other non-protic solvent, and is then treated with thephosphonate reagent, 245.9, bearing a leaving group, for example,bromine, mesyl, tosyl, or trifluoro-methanesulfonyl in the presence of asuitable organic or inorganic base.

For example, 245.10 dissolved in DMF, is treated with one equivalent ofsodium hydride and one equivalent of(toluene-4-sulfonylmethyl)-phosphonic acid dibenzyl ester 245.11,prepared according to the procedures in J. Org. Chem. 1996, 61, 7697, togive CsA phosphonate 245.5. Using the above procedure but employingdifferent phosphonate reagents, 245.9, in place of compound, 245.11,there are obtained the corresponding products, 245.1, bearing differentlinking groups.

Example 246

The preparation of CsA—phosphonate conjugates is illustrated above. Thehydroxyl group of amino acid 1 is first protected with a suitableprotecting group, for example silyl ethers, benzyl ethers, trityl ethersetc as described in Greene and Wuts, “Protecting Groups in OrganicSynthesis,” 3^(rd) Edition, John Wiley and Sons, Inc. The protectedproduct, 246.1, is then treated with an oxidizing agent, many examplesof which are described in “Comprehensive Organic Transformations,” JohnWiley & Sons, 2^(nd) Ed, R. C. Larock, p 1211-1215 to give the aldehyde,246.2.

Aldehyde, 246.2, is then treated with a amine phosphonic acid ester ofthe general formula 246.3 under reductive amination conditions to affordamine, 246.4. The preparation of amines by means of reductive aminationprocedures is described, for example, in “Comprehensive OrganicTransformations,” by R. C. Larock, 2^(nd) edition, p. 835. In thisprocedure, the amine component and the aldehyde component are reactedtogether in the presence of a reducing agent such as, for example,borane, sodium cyanoborohydride or diisobutylaluminum hydride, to yieldthe amine product. Finally, deprotection of the hydroxyl group followingprocedures documented in Greene and Wuts, “Protecting Groups in OrganicSynthesis,” 3^(rd) Edition, John Wiley and Sons Inc. p 116-121 gives thephosphonate 246.5.

Example 247

For example, 245.10, is treated in pyridine and dichloromethane withtrimethylsilyl chloride, as described in U.S. Pat. No. 6,410,696 B1, togive silyl ether, 247.1. Silyl ether, 247.1, is then treated with ozonefollowed by work up with dimethyl sulfide to give aldehyde 247.2.Aldehyde, 247.2, is treated with one equivalent of the hydrochloridesalt of (2-amino-ethyl)-phosphonic acid ester diethyl ester, 247.3,prepared according to J. Med. Chem., 1998, 41, 23, p 4439, and asuitable base, e.g. hunigs base, triethylamine, or the likes, until theimine is formed. The intermediate imine solution is then treated withsodium cyanoborohydride to give the amine, 247.4. Amine, 247.4, is thendeprotected by treatment with TBAF in an aprotic solvent such as THF ordioxane to give phosphonate, 247.5. Using the above procedure butemploying different phosphonate reagents, 246.3, in place ofphosphonate, 247.3, there are obtained the corresponding products,246.5, bearing different linking groups.

Example 248

The preparation of CsA phosphonate conjugates where the phosphonate islinked onto the alanine nitrogen in amino acids 7 and 8, compounds,245.3 and 245.4, is illustrated herein. Protected CsA, 246.1 (Example246), is treated with a base, sufficiently basic to remove the amideproton, for example, metal hydrides, metal amides. The product is thentreated with a phosphonate reagent, 245.9, bearing a leaving group suchas, for example, bromine, mesyl, tosyl, or trifluoromethanesulfonylphosphonates, to give 248.1 and 248.2. The alkylated products are thenseparated by chromatography and independently deprotected usingconventional conditions described in Greene and Wuts, “Protecting Groupsin Organic Synthesis,” 3^(rd) Edition, John Wiley and Sons Inc. p116-121 to give compounds having Formulae, 245.3 and 245.4.

Example 249

Silyl ether, 247.1, in toluene is treated with sodium hydride and15-crown-5-ether followed by one equivalent of bromomethyl phosphonicacid diallyl ester, 249.1 (Lancaster), to give phosphonates, 249.2 and249.3, respectively. Phosphonates, 249.2 and 249.3, are deprotected bytreatment with TBAF in an aprotic solvent such as THF or dioxane to givecompounds having Formulae, 249.4 and 249.5, respectively, wherein thelinkage is a methylene group. Using the above procedure but employingdifferent phosphonate reagents, 245.9, in place of phosphonate reagents,249.1, there are obtained the corresponding products having Formulae,245.3 and 245.4, with different linking groups.

Example 250

The preparation of compounds of the invention having phosphonate groupsand intermediate compounds useful for their synthesis are illustratedherein. The substructure on the right is meant to represent CyclosporinA in the following examples.

Example 251cyclo-[[(2S,3R,4R,6E)-7-(4-Acetoxyphenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]

A mixture of cyclosporin A (360 mg, 0.3 mmol), 4-acetoxystyrene (730 mg,4.5 mmol) and(1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidene)dichloro-(O-isopropoxyphenylmethylene)ruthenium(Hoveyda-Grubbs catalyst, 20 mg, 0.032 mmol) in dichloromethane (1 mL)was purged with nitrogen and stirred under reflux for 16 hours. Aftercooling, the reaction mixture was purified by silica gel columnchromatography using MeOH—CH₂Cl₂ to provide the product as a solid (395mg, 99%).

MS (m/z) 1322.9 [M+H]⁺, 1344.9 [M+Na]⁺; HPLC retention time 3.3 min.(relative to 4.1 min. of cyclosporin A; Phenominex Synergi 4 micronhydro-RP 80A 50×4.6 mm; solvents, 35% water and 65% acetonitrile; flowrate 2 mL/min.; column temperature 60° C.).

Example 252cyclo-[[(2S,3R,4R,6E)-7-(4-Hydroxyphenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]

A solution ofcyclo-[[(2S,3R,4R,6E)-7-(4-acetoxyphenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl](385 mg, 0.29 mmol) and triethylamine (1 mL) in MeOH (10 mL) was stirredat ambient temperature for 16 hours. The reaction mixture wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography using MeOH—CH₂Cl₂ to provide the desired product (310 mg,83%).

MS (m/z) 1280.9 [M+H]⁺, 1278.8 [M−H]⁻; HPLC retention time 1.6 min.(relative to 4.0 min. of cyclosporin A; Phenominex Synergi 4 micronhydro-RP 80A 50×4.6 mm; solvents, 35% water and 65% acetonitrile; flowrate 2 mL/min.; column temperature 60° C.).

Example 253cyclo-[[(2S,3R,4R,6E)-7-(4-(Diethoxyphosphorylmethoxy)-phenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-amino-butyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]

To a mixture ofcyclo-[[(2S,3R,4R,6E)-7-(4-hydroyphenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl](113 mg, 0.088 mmol) and cesium carbonate (33 mg, 0.1 mmol) in DMF (1mL) was added trifluoromethanesulfonic acid diethoxyphosphorylmethylester (60 mg, 0.2 mmol). The mixture was stirred at room temperature for16 hours. The reaction was quenched with 2% aqueous lithium chloride andthe mixture was extracted with ethyl acetate. The ethyl acetate extractwas concentrated in vacuo. The residue was purified by silica gel columnchromatography to provide the desired product (310 mg, 83%) contaminatedwith the unreacted starting materials, which was further purified by RPHPLC using a Phenomenex Synergi 5μ Hydro RP 80A column (50×21.2 mm) witheluents of H₂O—CH₃CN. The fractions containing the desired product werepooled and concentrated to dryness (62 mg, 49%).

MS (m/z) 1431.0 [M+H]⁺, 1428.7 [M−H]⁻; ³¹P (121.4 MHz, CDCl₃) δ 19.5.

Example 254cyclo-[[(2S,3R,4R,6E)-7-(4-(Dibenzyloxyphosphorylmethoxy)phenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]

To a mixture ofcyclo-[[(2S,3R,4R,6E)-7-(4-hydroyphenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl](300 mg, 0.234 mmol) and cesium carbonate (326 mg, 1 mmol) in DMF (2 mL)was added trifluoromethanesulfonic acid dibenzyloxyphosphorylmethylester (60 mg, 0.2 mmol). The mixture was stirred at room temperature for16 hours. The reaction mixture was filtered through Acrodisc (13 mmsyringe filter with 0.45 micron Nylon membrane) and purified by RP HPLCusing a Phenomenex Synergi 5μ Hydro RP 80A column (50×21.2 mm) witheluents of H₂O—CH₃CN. The fractions containing the desired product werepooled and concentrated to dryness, affording a white solid (115 mg,32%).

MS (m/z) 1554.9 [M+H]⁺, 1552.7 [M−H]⁻; ³¹P (121.4 MHz, CDCl₃) δ 20.5.

Example 255cyclo-[[(2S,3R,4R,6E)-7-(4-(Dihydroxyphosphorylmethoxy)phenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]

To a mixture ofcyclo-[[(2S,3R,4R,6E)-7-(4-(dibenzyloxyphosphorylmethoxy)phenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl](115 mg, 0.074 mmol) and 2,6-lutidine (40 μL, 0.35 mmol) indichloromethane (2 mL) was added trimethylsilyl bromide (50 μL, 0.35mmol). The mixture was stirred at room temperature for 2 hours. Thereaction was quenched with methanol (1 mL) and the mixture wasconcentrated. The residue was treated with a solution of ammoniumfluoride (0.5 M, 2 mL), stirred for 1 hour, concentrated, andpartitioned between dichloromethane and 1 N HCl. The dichloromethanelayer was concentrated and the crude product was purified by RP HPLCusing a Phenomenex Synergi 5μ Hydro RP 80A column (50×21.2 mm) witheluents of 0.1% TFA H₂O—0.1% TFA CH₃CN. The fractions containing thedesired product were pooled and concentrated to dryness, affording ahygroscopic solid (68 mg, 63%).

MS (m/z) 1374.9 [M+H]⁺, 1373.1 [M−H]⁻; HPLC retention time 0.3 min.(relative to 4.0 min. of cyclosporin A; Phenominex Synergi 4 micronhydro-RP 80A 50×4.6 mm; solvents, 35% water and 65% acetonitrile; flowrate 2 mL/min.; column temperature 60° C.).

Example 256cyclo-[[(2S,3R,4R,6E)-7-(4-(1-(S)-Ethoxycarbonylethoxy)-phenoxyphosphorylmethoxy)phenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]

A mixture ofcyclo-[[(2S,3R,4R,6E)-7-(4-(dihydroxyphosphorylmethoxy)phenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl](34 mg, 0.023 mmol), phenol (22 mg, 0.23 mmol), dicyclohexylcarbodiimide(47 mg, 0.23 mmol) and 4-(N,N-dimethylamino)pyridine (5.6 mg, 0.046mmol) in DMF (2 mL) was stirred at 140° C. for 20 min. After cooling,the monophenyl mono-phosphonic acid product was purified by RP HPLCusing a Phenomenex Synergi 5μ Hydro RP 80A column (50×21.2 mm) witheluents of 0.1% TFA H₂O—0.1% TFA CH₃CN. MS (m/z) 1450.9 [M+H]⁺, 1449.1[M−H]⁻; ³¹P (121.4 MHz, CDCl₃) δ 14.9. This intermediate was mixed withethyl (S)-(−)-lactate (40 mg, 0.34 mmol), PyBOP (80 mg, 0.15 mmol),diisopropylethylamine (45 μL, 0.26 mmol) and DMF (1.7 mL). The resultingmixture was stirred at room temperature for 2 hours. After removal ofinsoluble impurities, the crude product was purified by RP HPLC using aPhenomenex Synergi 5μ Hydro RP 80A column (50×21.2 mm) with eluents of0.1% TFA H₂O—0.1% TFA CH₃CN. The desired fractions were pooled andpartitioned between acetonitrile and saturated aqueous sodiumbicarbonate. The organic layer was concentrated to afford the product asa solid (12 mg, 34%).

MS (m/z) 1573.1 [M+Na]⁺, 1548.8 [M−H]⁻; ³¹P (121.4 MHz, CDCl₃) δ 15.3and 17.4.

Example 257cyclo-[[(2S,3R,4R,6E)-7-(4-(1-(S)-Hydroxycarbonylethoxy)-hydroxyphosphorylmethoxy)phenyl)-4-methyl-3-hydroxy-2-(methylamino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]

To a solution ofcyclo-[[(2S,3R,4R,6E)-7-(4-(1-(S)-ethoxycarbonylethoxy)phenoxyphosphorylmethoxy)phenyl)-4-methyl-3-hydroxy-2-(methyl-amino)-6-heptenoyl]-L-2-aminobutyryl-sarcosyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl](5 mg, 3.2 μmol) in a mixed solvent of water and acetonitrile (0.5 mLand 4.5 mL) was added 1 N NaOH (40 μL). The solution was stirred at roomtemperature for 2 hours. The resulting reaction mixture was concentratedand purified by RP HPLC using a Phenomenex Synergi 5μ Hydro RP 80Acolumn (50×21.2 mm) with eluents of 0.1% TFA H₂O—0.1% TFA CH₃CN. Thedesired fraction was concentrated to dryness affording the product as asolid (1.5 mg, 32%).

MS (m/z) 1446.9 [M+H]⁺, 1444.9 [M−H]⁻; HPLC retention time 0.2 min.(relative to 4.0 min. of cyclosporin A; Phenominex Synergi 4 micronhydro-RP 80A 50×4.6 mm; solvents, 35% water and 65% acetonitrile; flowrate 2 mL/min.; column temperature 60° C.).

Example 258

The synthesis of compounds of the invention that are analogs of BCX-1777is shown herein.

Compounds of the invention, such as, for example, 258.1 can be madeaccording to the general route outlined herein.

Example 259

The Boc-protected(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol, compound,259.1, is prepared by stirring the(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol (WO9,919,338 and Evans, G. B. et al., Tetrahedron, 2000, 56, 3053, alsoreported in Evans, G. B. et al., J. Med. Chem. 2003, 46, 3412) with BOCanhydride as described in Greene, T., “Protective Groups in OrganicSynthesis,” Wiley-Interscience, 1999. Compound, 259.1, is then treatedin a solvent such as tetrahydrofuran or dimethylformamide with a basesuch as sodium hydride. When bubbling ceases, diethylphosphonomethyl-triflate (prepared according to Tetrahedron Lett., 1986,27, 1477) is added, yielding the desired phosphonate, 259.2, afterdeprotection of the BOC group using trifluoroacetic acid (TFA).

Example 260

Compounds such as 260.1 and 260.2 can be made according to the generalroute outlined herein.

Example 261

The Boc-protected(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol, compound,259.1, is prepared by stirring the(1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol (WO9,919,338 and Evans, G. B. et al., Tetrahedron, 2000, 56, 3053, alsoreported in Evans, G. B. et al., J. Med. Chem. 2003, 46, 3412) with BOCanhydride as described in Greene, T., “Protective Groups in OrganicSynthesis,” Wiley-Interscience, 1999. Subsequent protection of theprimary alcohol using a TBS group can be achieved using TBSCl andimidazole in solvents such as CH₂Cl₂ as described in Greene, T.,“Protective Groups in Organic Synthesis,” Wiley-Interscience, 1999 toprovide compound, 261.1. Compound, 261.1, is then treated in a solventsuch as tetrahydrofuran or dimethylformamide with a base such as sodiumhydride. When bubbling ceases, diethyl phosphonomethyltriflate (preparedaccording to Tetrahedron Lett., 1986, 27, 1477) is added, yielding amixture of the desired phosphonate diester, 261.2, and 261.3, afterdeprotection of the BOC group using trifluoroacetic acid (TFA).Compounds, 261.2, and 261.3, can be also prepared via a more complicated2′ OH protected analog of compound 261.1 followed by alkylation usingthe diethyl phosphonomethyltriflate to provide compound 261.2,exclusively. Compound 261.3 can also be prepared by installation of adifferent protecting group at the 3′ OH position, followed bydeprotection of 2′ OH and alkylation with diethylphosphonomethyltriflate at the 2′ center followed by globaldeprotection.

Example 262

Representative compounds of the invention can be prepared as illustratedabove. Derivatization at the C-11 hydroxy group is accomplished throughalkylation of methylprednisolone aceponate 262.1 with the appropriatephosphonate, furnishing analogs of formula 262.2. A specific compound ofthe invention can be prepared as follows.

After sodium hydride extraction of the hydroxy proton in 262.1, diethylphosphonate triflate is added to afford ether 262.3.

Example 263

Representative compounds of the invention can be prepared as illustratedabove by exploiting the reactivity differences among the three hydroxygroups available when methylprednisolone aceponate, 262.1, is fullyhydrolized. Following protection of the only exposed hydroxy group in262.1, intermediate, 263.1 is saponified to give diol, 263.2. Alkylationat the primary hydroxy group with the appropriate phosphonate andsubsequent acylation provides the propionate ester, 263.4. The desiredproduct, 263.5, is achieved after deprotection.

Example 264

Methylprednisolone aceponate, 262.1, is protected as its silyl etherusing the standard TBSCl and imidazole conditions. (J. Am. Chem. Soc.,1972, 94, 6190). Saponification of both ester moieties using aqueoussodium hydroxide provides the diol, 264.2. The less sterically hinderedprimary hydroxy group is alkylated by the addition of sodium hydroxideand the phosphonate triflate. After treating intermediate, 264.3, withpropionic anhydride in pyridine, the previously hydrolized C-17propionic ester is replaced. (J. Med. Chem., 1980, 23, 430-437). TBAFdeprotection of the silyl ether furnishes diethyl phosphonate 264.5.

Example 265

Representative compounds of the invention can be prepared as illustratedabove. The two hydroxy groups of diol, 263.2, are regioselectivelydifferentiated by protection at the primary site, thus allowingalkylation at the tertiary hydroxy group. The resulting phosphonateintermediate, 265.2, is then deprotected to afford the diol 265.3. Againthe more accessible primary hydroxy group is acylated to produce thedesired analog 265.4.

Example 266

Diol, 264.2 (see example 264), is protected at the primary site as itssilyl ether, 266.1. Following alkylation with the diethyl phosphonatetriflate, the resulting intermediate, 266.2, is treated with TBAF togive diol, 266.3. Acetic anhydride and pyridine are used to generate thefinal product 266.4. (J. Mol. Biol., 1972, 72, 219).

Example 267

Representative compounds of the invention can be prepared as illustratedabove. The phosphorus containing merimepodib analog 267.2 is synthesizedfrom parent compounds by alkylation. Merimepodib 267.1 is obtained bythe procedure as described in U.S. Pat. No. 6,054,472 and U.S. Pat. No.6,344,465. The methoxy group of merimepodib 267.1 is demethylated tophenolic OH using a suitable reagent, such as boron tribromide. Thephosphonate moiety is introduced to the phenolic OH in a suitableaprotic solvent such as, DMF and is then treated with the phosphonatereagent bearing a leaving group, for example, bromine, mesyl, tosyl, ortrifluoromethanesulfonyl, in the presence of a suitable organic orinorganic base. A specific compound of the invention can be prepared asfollows.

A solution of 267.1 in dichloromethane is treated with boron tribromideto obtain the demethylated compound 267.8. Compound 267.8 is thentreated with cesium carbonate and one equivalent of(trifluoromethanesulfonyloxy)-methylphosphonic acid diethyl ester 267.9to give merimepodib-phosphonate 267.10. Using the above procedure butemploying different phosphonate reagents, the corresponding products267.2 bearing different linking group can be obtained.

Example 268

Representative compounds of the invention can be prepared as illustratedabove. The imidazole containing intermediate 268.13 is synthesized froman aldehyde 268.12 by the procedure of Shih in Tetrahedron Lett. 1993,34, 595. Compound 268.12 is prepared by a two-step procedure describedin U.S. Pat. No. 5,807,876, U.S. Pat. No. 6,054,472, and U.S. Pat. No.6,344,465. The imidazole is protected using suitable reagent, forexample, 2-(trimethylsilyl)-ethyoxymethyl (SEM) chloride, and thecompound 268.14 is converted to 268.15 by the similar proceduredescribed for the synthesis of 197.1 in U.S. Pat. No. 6,054,472 and U.S.Pat. No. 6,344,465. After the protecting group on the imidazole of268.15 is removed, the phosphonate containing moiety is introduced tothe imidazole to provide compounds of the invention. A specific compoundof the invention can be prepared as follows.

Compound 268.15 is treated with tetrabutylammonium fluoride in THF inreflux condition and the resulting 268.16 is alkylated with 268.9 usingsodium hydride as a base to obtain two isomers 268.17 and 268.18, whichare separated by chromatography.

Example 269

Representative compounds of the invention can be prepared as illustratedabove. Tetrasubstituted benzene derivatives are obtained by literatureprocedures (Ichikawa and Ichibagase Yakugaku Zasshi 1963, 83, 103;Norio, A. et al. Tetrahedron Lett. 1992, 33(37), 5403). After thephenolic OH is protected with a suitable protecting group, for examplebenzyl group, the compound 269.21 is synthesized by the same proceduredescribed in U.S. Pat. No. 6,054,472, and U.S. Pat. No. 6,344,465. Afterthe protecting group is removed, the phosphonate containing moiety isintroduced to the phenolic OH using the phosphonate reagent 269.7,bearing a suitable leaving group. A specific compound of the inventioncan be prepared as follows.

For example, a solution of 269.22, which is obtained by the procedure ofNorio et al. (Tetrahedron Lett. 1992, 33(37), 5403), is treated withsodium hydride and one equivalent of benzyl bromide in DMF to get269.23. Compound 269.23 is converted to 269.24 by a series of steps suchas those reported in U.S. Pat. No. 6,054,472, and U.S. Pat. No.6,344,465. After the benzyl protecting group of 269.24 is removed bycatalytic hydrogenation, a phosphonate bearing moiety is attached byalkylation of the resulting phenol in DMF using sodium hydride and oneequivalent of (trifluoromethanesulfonyl-oxy)methylphosphonic aciddiethyl ester 269.9 to give 269.25.

Example 270

Representative compounds of the invention can be prepared as illustratedabove. Compound 270.26 is treated with carbonyldiimidazole ortriphosgene followed by the compound 270.27, which has a handle toattach phosphonate moiety. Compound 270.27 bearing an extra substituentis synthesized from the tri substituted phenol with a cyano and a nitrogroups, which is either commercially available or by literatureprocedures (Zolfigol, M. A. et. al. Indian J. Chem. Sect. B 2001, 40,1191; De Jongh, R. O. et al. Recl. Trav. Chim. Pays-Bas 1968, 87, 1327).The resulting 270.28 is converted to 270.29 using procedures similar tothose described in U.S. Pat. No. 6,054,472, and U.S. Pat. No. 6,344,465.The phosphonate moiety of 270.6 is attached after deprotection of thebenzyl group of 270.29.

For example, the bromine substituent of compound 270.30 is substitutedwith cyano group by the procedure of De Jongh, R. O. et al. (Recl. Trav.Chim. Pays-Bas 1968, 87, 1327) and the methoxy group is converted tobenzyloxy group as a protecting group, which affords compound 270.31.After selective reduction of cyano to aminomethyl group by borane, theamino group is protected with Boc group and then the reduction of thenitro group using tin (II) chloride generates compound 270.32. Thissubstituted aniline 270.32 is then treated with a reaction mixture ofthe compound 270.26 and carbonyldiimidazole, as described in U.S. Pat.No. 6,054,472, and U.S. Pat. No. 6,344,465, to form the urea 270.33.Compound 270.33 is converted to 270.34. Deprotection of the benzyl groupusing catalytic hydrogenation followed by attachment of a phosphonatemoiety using 270.9 in the presence of cesium carbonate produces compound270.35.

Example 271

The syntheses of phosphonate compounds of the invention and ofintermediate compounds necessary for their synthesis are illustratedherein. Derivatization at the C-21 hydroxy group is accomplished throughalkylation of dexamethasone 271A with the appropriate phosphonate,furnishing analogs shown herein.

Derivatization at the C-21 hydroxy group is accomplished throughalkylation of dexamethasone 271A with the appropriate phosphonate,furnishing analogs of the type 271.2.

After sodium hydride extraction of the primary hydroxy proton in 271A,diethyl phosphonate triflate is added to afford ether 271.5.

Example 272

Synthesis of C-21 phosphonate analogs having formula, 271.4, is shownherein. Protection this time of dexamehtasone 271A at the less hinderedsite furnishes alcohol, 271.5, which is alkylated at the only exposedhydroxy group with the appropriate phosphonate. Removal of theprotecting groups completes the construction of analog, 271.4.

Example 272

Dexamethasone, 271A, is protected as its silyl ether using the standardTBSCl and imidazole conditions. (J. Am. Chem. Soc., 1972, 94, 6190;however, harsher conditions should allow for bis-protection. Afteralkylating with the diethyl phosphonate triflate, the resultingintermediate, 271.9, is treated with TBAF to give the desiredphosphonate, 271.10.

Example 273

A number of compounds of the general structure 273A can either beprepared using procedures described in the literature, or be purchasedfrom commercial sources. The following are good sources for informationon the art of preparing a variety of compounds, of the general structure273A, Townsend, Chemistry of Nucleosides and Nucleotides, Plenum Press,1994; and Vorbruggen and Ruh-Pohlenz, Handbook of Nucleoside Synthesis,John Wiley & Sons, Inc., 2001.

In the examples the compounds of the invention, described herein, thesubstituents have the following general formula 273A:

wherein one or more of the Z substituents have been substituted with anA⁰ group; and wherein:

Z₁ and Z₂ are independently selected from hydrogen, or a C₁-C₁₈ acyl,and Z₃ is H, a C₁-C₁₈ acyl, or

or Z₁ is hydrogen, and together Z₂ and Z₃ are

base is

wherein X and Y are independently O or S; Z⁴ is hydrogen, amino,hydroxy, or a halogen selected from Cl and Br.

More specifically, the preparation of generic structure, 273A aredescribed in Nagahara, et al J. Med. Chem.; 33; 1990; 407-415. Thestructure 273.2 is described in Kini, et al J. Med. Chem.; 34; 1991;3006-3010. The two patents cited above also provided examples of thesynthesis of compound, 273A.

The core components of this reaction sequence are the transformation ofcompound from 273.3 to 273.6. Appropriate oxidant(s) can convert theprimary alcohol (5′-hydroxy) shown in 273.3 to a carboxylic acid or itscorresponding ester. In the case of an ester, an additional deprotectionstep will give the carboxylic acid, 273.4. A variety of oxidationprocedures exist in the literature and can be utilized here. Theseinclude but are not limited to the following methods: (i) pyridiniumdichromate in Ac₂O, t-BuOH, and dichloromethane producing the t-butylester, followed by a deprotection using reagent such as trifluoroaceticacid to convert the ester to the corresponding carboxylic acid (seeClasson, et al., Acta Chem. Scand. Ser. B; 1985, 39, 501-504. Cristalli,et al., J. Med. Chem., 1988, 31, 1179-1183.); (ii) iodobenzene diacetateand 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO) inacetonitrile, producing the carboxylic acid (See Epp, et al; J. Org.Chem. 64; 1999; 293-295. Jung et al; J. Org. Chem.; 66; 2001;2624-2635.); (iii) sodium periodate, ruthenium(III) chloride inchloroform producing the carboxylic acid (see Kim, et al, J Med. Chem.37; 1994; 4020-4030. Homma, et al; J. Med. Chem., 35; 1992; 2881-2890);(iv) chromium trioxide in acetic acid producing the carboxylic acid (seeOlsson et al; J. Med. Chem.; 29; 1986; 1683-1689. Gallo-Rodriguez et al;J. Med. Chem.; 37; 1994; 636-646); (v) potassium permanganate in aqueouspotassium hydroxide producing the carboxylic acid (see Ha, et al; J.Med. Chem.; 29; 1986; 1683-1689. Franchetti, et al; J. Med. Chem.; 41;1998; 1708-1715.) (vi) nucleoside oxidase from S. maltophilia to givethe carboxylic acid (see Mahmoudian, et al; Tetrahedron; 54; 1998;8171-8182.)

The preparation of compound 273.5 starting with compound 273.4 usinglead(IV) tetraacetate (Lv=OAc) was described by Teng et al; J. Org.Chem., 59; 1994; 278-280 and Schultz, et al; J. Org. Chem.; 48; 1983;3408-3412. When lead(IV) tetraacetate is used together with lithiumchloride (see Kochi, et al; J. Am. Chem. Soc.; 87; 1965; 2052), thecorresponding chloride is obtained (273.5, Lv=Cl). Lead(IV) tetraacetatein combination with N-chlorosuccinimide can produce the same product(273.5, Lv=Cl) (see Wang, et al; Tet. Asym.; 1; 1990; 527 and Wilson etal; Tet. Asym.; 1; 1990; 525). Alternatively, the acetate leaving group(Lv) can also be converted to other leaving group such as bromide bytreatment of trimethylsilyl bromide to give 273.5 ((see Spencer, et al;J. Org. Chem.; 64; 1999; 3987-3995).

The coupling of 273.5 (Lv=OAc) with a variety of nucleophiles weredescribed by Teng et al; Synlett; 1996; 346-348 and U.S. Pat. No.6,087,482; Column 54 line 64 to Column 55 line 20. Specifically, thecoupling between 273.5 and diethyl hydroxymethylphosphonate in thepresence of trimethylsilyl trifluoromethanesulfonate (TMS-OTf) wasdescribed. It can be envisioned that other compounds with the generalstructure of HO-linker-POR^(P1)R^(P2) can also be used so long as thefunctional groups in these compounds are compatible with the couplingreaction conditions. There are many examples in the published literaturedescribing the coupling of 273.5 (Lv=halogen) with a variety ofalcohols. The reactions can be facilitated with a number of reagents,such as silver(I) salts (see Kim et al; J. Org. Chem.; 56; 1991;2642-2647, Toikka et al; J. Chem. Soc. Perkins Trans. 1; 13; 1999;1877-1884), mercury(II) salts (see Veeneman et al; Recl. Trav. Chim.Pays-Bas; 106; 1987; 129-131), boron trifluoride diethyl etherate (seeKunz et al; Hel. Chim Acta; 68; 1985; 283-287), Tin(II) chloride (seeO'Leary et al; J. Org. Chem.; 59; 1994; 6629-6636), alkoxide (seeShortnacy-Fowler et al; Nucleosides Nucleotides; 20; 2001; 1583-1598),and iodine (see Kartha et al; J. Chem. Soc. Perkins Trans. 1; 2001;770-772). These methods can be selectively used in conjunction withdifferent methods in forming 273.5 with various leaving groups (Lv) toproduce 273.6.

The transformations from 273.1 to 273.2, from 273.2 to 273.3, and from273.6 to 273.7 are intended to allow the core components of thetransformations (from 273.3 to 273.6) to occur while preserving thefunctional groups already exist in the compound structures. Thus, thesyntheses may require the introduction and removal of protecting groupsfrom a compound is a commonly practiced art in organic synthesis. Itshould be understood that in the transformation 273.6 to 273.7, R^(P1)and R^(P2) do not need to remain unchanged. The final form of R^(P1) andR^(P2) can be selected from a variety of possible structures.

Example 274

Compound 274.1 is prepared using the method described in the patentapplication WO 01/90121 (table at page 115). The 5′-hydroxyl in 274.1 isprotected as a tert-butyldimethylsilyl (TBDMS) ether. The 2′- and3′-hydroxyl groups can be protected as bezoyl (Bz) esters to give 274.2.The 5′-hydroxyl can then be deprotected to give 274.3. Oxidation usingiodobenzene diacetate and 2,2,6,6-tetramethyl-1-piperidinyloxy, freeradical (TEMPO) convert the primary alcohol to the corresponding acid274.4. Further oxidation of 274.4 using lead tetraacetate can produce274.5. Coupling between 274.5 and diethyl hydroxy-methyl-phosphonate(available from Sigma-Aldrich, Cat. No. 39, 262-6) effected by TMS-OTfcan afford 274.6. Treating 274.6 with TMS-Br converts the phosphodiesterto the corresponding phosphonic acid 274.7. Deprotection of the 2′- and3′-hydroxyl gives 274.8 as an example of the generic structure A, whereBase is an 7-thia-8-oxo-guanosine, R¹, R², R^(P1) and R^(P2) arehydrogen, linker is a methylene group.

The phosphonic acids in 274.7 and 274.8 are used as examples forillustration purpose. Other forms of phosphonates can be access via thephosphonic acid, or other forms, such as the corresponding diesters asdescribed herein.

Example 275

Leflunomide (structure below, together with its active metabolite) (seeU.S. Pat. No. 4,284,786) is a derivative of isoxazole. Representativecompounds of the invention can be prepared as illustrated above usingprocedures similar to those described in J. Med. Chem. 1996, 39, 4608.Their structures are shown below.

Synthetic methodology towards compounds such as these is described byWestwood et al, J. Med. Chem., 1996, 39, 4608-4621, according to thegeneral routes outlined below.

Example 275A

The synthesis of suitable phosphonate-containing anilines are shownbelow.

Example 275B

Example 276

Representative compounds of the invention can be prepared as illustratedabove using procedures similar to those described in J. Med. Chem. 1996,39, 4608. Treatment of compound of the invention 276.1 with baseprovides compound 276.2 which is also a compound of the invention.

Example 277

Representative compounds of the invention can be prepared as illustratedabove. Treatment of compound of the invention 277.1 with base providescompound 277.2 which is also a compound of the invention.

Example 278

Example 278A Synthesis of K-105-44

2-Methyl-5-nitrophenol (2.00 g, 13.05 mmol) was dissolved in dry DMF (10mL) under argon atmosphere and cooled to 0° C.Diethylphosphonomethyl-O-triflate (4.70 gm, 15.66 mmol) and cesiumcarbonate (6.38 gm, 19.58 mmol) were added sequentially. The reactionmixture was stirred at 0° C. for 4 hrs. TLC (cyclohexane/EtOAc, 1:1)showed completion of reaction. Deionized water (15 mL) was added and themixture was extracted with EtOAC (2×50 mL). The organic layer was washedwith 1N HCl (20 mL) followed by water (2×20 mL), dried over Na₂SO₄ andconcentrated to a semi-solid. Purification by silica gel columnchromatography (cyclohexane/EtOAc, 1:1) afforded pure compound K-105-44as an oil (3.86 g, 97%).

ESI-MS m/z 304 [M+H]⁺.

Example 278B Synthesis of K-105-48

Compound K-105-44 (2.8 g, 9.24 mmol) was dissolved in 15 mL of absoluteethanol (15 mL) and 6N HCl (2 mL) under an argon atmosphere. Followingthe addition of SnCl₂.2H₂O (5.26 g, 27.72 mmol), the reaction mixturewas stirred overnight at room temperature. TLC (CHCl₃/MeOH, 9:1) showedcompletion of reaction. The mixture was concentrated to a semi-solid anddissolved in ethyl acetate (30 mL). The ethyl acetate layer was washedwith deionized water (10 mL) and satd. NaHCO₃ (10 mL) and dried overNa₂SO₄. Concentration gave a solid that was used without purification.

ESI-MS m/z 274 [M+H]⁺.

Example 278C Synthesis of K-105-49-3

Crude compound K-105-48 (900 mg, 3.38 mmol) was dissolved in 15 mL ofdry THF (15 mL) under an argon atmosphere. Following the addition of5-methylisoxazole-4-carboxylic acid (381 mg, 3.00 mmol) and diisopropylcarbodiimide (511 μL, 3.30 mmol), the reaction mixture was stirred 6 hat room temperature. TLC (CHCl₃/MeOH, 9:1) showed completion ofreaction. The reaction mixture was filtered and the filtrateconcentrated to give a solid, which was dissolved in ethyl acetate (25mL). The solution was washed with deionized water (2×10 mL) and driedover Na₂SO₄. Concentration gave a solid that was purified by silica gelcolumn chromatography (CHCl₃/MeOH, 95:5) to afford pure compoundK-105-49-3 as light yellow solid (680 mg, 55%).

ESI-MS m/z 383 [M+H]⁺.

¹H NMR (300 MHz, CDCl₃): δ 7.11 (1H, s, ArH), 7.06 (2H, s, ArH),4.29-4.20 (4H, m, OCH₂), 4.14 (2H, d, J=10.4 Hz, OCH₂), 2.76 (3H, s,CH₃), 2.14 (3H, s, CH₃), 1.37 (6H, t, J=7.0 Hz, CH₃).

³¹P NMR (121.7 MHz, DMSO-d₆/external H₃PO₄) δ ppm 19.7-20.0 (m)

HPLC: 98% pure (Sphereclone 5 μL, H₂O: MeCN, 20 min linear from 10-90%MeCN, 1.0 mL/min)

Example 278D Synthesis of K-105-54-1

Compound K-105-54-1 (250 mg, 0.65 mmol) was dissolved in 10 mL ofabsolute ethanol (15 mL) under an argon atmosphere. Following theaddition of NaOH (29 mg, 0.72 mmol), the reaction mixture was stirredovernight at room temperature. TLC (CHCl₃/MeOH, 9:1) showed completionof reaction. The reaction mixture was concentrated to a solid anddissolved in ethyl acetate (20 mL). The solution was washed withdeionized water (2×10 mL) and dried over Na₂SO₄. Concentration gave asolid that was purified by silica gel column chromatography (CHCl₃/MeOH,4:1), affording pure compound K-105-54-1 as a solid (188 mg, 75%).

ESI-MS m/z 383 [M+H]⁺.

¹H NMR (300 MHz, DMSO-d₆): δ 7.32 (1H, s, ArH), 6.96 (2H, s, ArH), 4.31(2H, d, J=9.9 Hz, OCH₂), 4.18-4.08 (4H, m, 2×OCH₂), 2.08 (3H, s, CH₃),2.00 (3H, s, CH₃), 1.26 (6H, t, J=7.0 Hz, CH₃). ³¹P NMR (121.7 MHz,DMSO-d₆/external H₃PO₄) δ ppm 20.0-20.4 (m)

HPLC: 93% pure (Sphereclone 5 μL, H₂O: MeCN, 20 min linear from 10-90%MeCN, 1.0 mL/min)

Example 279

Representative compounds of the invention can be prepared as illustratedabove. Specific compounds of the invention can be prepared asillustrated below.

Example 280

Representative macrolide compounds of the invention, wherein thestructure 280.1 is understood to be the compound tacrolimus, ascomycinor sirolimus, can be prepared as illustrated above, for example, usingan aryl bismuth reagent such as that shown is described in Bioorg. Med.Chem. Lett, 1995, 5, 1035. Additionally, silver salts have been used tomediate alkylations on immunosuppresive macrolides such as these: see J.Med. Chem., 1998, 41, 1764. Specific compounds of the invention can beprepared as illustrated below.

Example 281

Representative macrolide compounds of the invention, wherein thestructure 212.1 is understood to be the compound tacrolimus, ascomycinor sirolimus, can be prepared as illustrated above, for example, usingan aryl bismuth reagent such as that shown is described in Bioorg. Med.Chem. Lett, 1995, 5, 1035. Additionally, silver salts have been used tomediate alkylations on immunosuppresive macrolides such as these: see J.Med. Chem., 1998, 41, 1764. Specific compounds of the invention can beprepared as illustrated below.

Example 282

Representative compounds of the invention can be prepared as illustratedabove. Derivatization at the C-21 hydroxy group is accomplished throughalkylation of prednisone 282.1 with the appropriate phosphonate toprovide compounds of the invention 282.2. A specific compound of theinvention can be prepared as follows.

After sodium hydride extraction of the primary hydroxy proton in 282.1,diethyl phosphonate triflate is added to afford ether 282.4.

Example 283

Representative compounds of the invention 283.3 can be prepared asillustrated above. Protection of prednisone 283.1 at the less hinderedprimary site furnishes alcohol 283.5, which is alkylated at the exposedhydroxy group with the appropriate phosphonate to provide 283.6. Removalof the protecting group completes the construction of analog 283.3. Aspecific compound can be prepared as follows.

Prednisone 283.1 is mono-protected as its TBS ether 283.7. Afteralkylating with the diethyl phosphonate triflate, the resultingintermediate 283.8 is treated with TBAF to give the desired phosphonate283.9.

The syntheses of phosphonate compounds of the invention and ofintermediate compounds necessary for their synthesis are illustratedherein. Derivatization at the C-21 hydroxy group is accomplished throughalkylation of dexamethasone 1 with the appropriate phosphonate,furnishing analogs shown herein.

Example 284

Representative compounds of the invention can be prepared as illustratedabove. Derivatization at the C-11 hydroxy group is accomplished throughalkylation of rimexolone 284.1 with the appropriate phosphonate,furnishing analogs of formula 284.2. A specific compound of theinvention can be prepared as illustrated below.

After sodium hydride extraction of the hydroxy proton in 284.1, diethylphosphonate triflate is added to afford ether 284.5.

Example 285

The diacid (100 mg, 0.304 mmol), amino acid (100 mg, 0.651 mmol), phenol(145 mg, 1.54 mmol), and triethylamine (510 μL, 3.66 mmol) weredissolved in pyridine (5 mL). The mixture was heated to 60° C. for 5minutes. To this reaction mixture was added a solution oftriphenylphosphine (560 mg, 2.14 mmol) and Aldrithiol(2) (470 mg, 2.13mmol) dissolved in pyridine (5 mL). The reaction was then heated at 60°C. for 12 hours. The reaction mixture was diluted in EtOAc, washed withH₂O, sat'd NaHCO₃(aq), and brine. The organic layer was dried (MgSO₄),concentrated and purified by chromatography on silica gel (1%MeOH/CH₂Cl₂→10% MeOH/CH₂Cl₂) to give monoamidate 130-1 (5 mg, 3%) andbisamidate 130-2 (5 mg, 3%).

For 130-1: ¹H NMR (300 MHz, CD₃OD) δ 7.78 (1H, m), 7.35 (2H, m), 7.20(3H, m), 4.18-3.95 (5H, m), 2.24-1.90 (2H, m), 1.87-1.62 (4H, m),1.38-1.18 (6H, m), 1.02 (6H, m); ³¹P NMR (121 MHz, CD₃OD) δ 36.3, 35.3;LC-MS (method: 0.5 min 95% H₂O/5% MeCN 5 min 0% H₂O/100% MeCN, rt=2.18min. MS calc'd for C₂₃H₃₄N₆O₅P (MH⁺): 505.2. Found 505.2.

For 130-2: ¹H NMR (300 MHz, CD₃OD) δ 7.77 (1H, s), 4.23-3.92 (8H, m),2.04-1.50 (6H, m), 1.42 (3H, d), 1.40 (3H, d), 1.28 (3H, t), 1.22 (3H,t), 1.02 (3H, s), 1.01 (3H, s); ³¹P NMR (121 MHz, CD₃OD) δ 33.9; LC-MS(method: 0.5 min 95% H₂O/5% MeCN 5 min 0% H₂O/100% MeCN, rt=1.79 min. MScalc'd for C₂₂H₃₉N₇O₆P (MH⁺): 528.3. Found 528.3.

Example 286

The diacid (25 mg, 0.072 mmol), amino acid (25 mg, 0.16 mmol), phenol(38 mg, 0.40 mmol), and triethylamine (127 μL, 0.911 mmol) weredissolved in pyridine (1.25 mL). The mixture was heated to 60° C. for 5minutes. To this reaction mixture was added a solution oftriphenylphosphine (140 mg, 0.534 mmol) and Aldrithiol(2) (119 mg, 0.540mmol) dissolved in pyridine (1.25 mL). The reaction was then heated at60° C. for 12 hours. Another batch of diacid (12 mg, 0.035 mmol) wastreated as described above. The reaction mixtures from both batches werecombined and diluted in EtOAc, washed with H₂O, sat'd NaHCO₃(aq) andbrine. The organic layer was dried (MgSO₄), concentrated and purified bychromatography on silica gel (1% MeOH/CH₂Cl₂ 10% MeOH/CH₂Cl₂). to givemonoamidate 133-1 (3 mg, 8%) and bisamidate 133-2 (8 mg, 20%).

For 133-1: ¹H NMR (300 MHz, CD₃OD) δ 8.38-8.08 (1H, m), 7.78-7.60 (2H,m), 7.50-7.18 (8H, m), 6.67-6.05 (1H, m), 5.60-5.30 (2H, m), 4.63 (1H,bs), 4.25-3.95 (3H, m), 1.37 (3H, m), 1.18 (3H, m); ³¹P NMR (121 MHz,CD₃OD) δ 21.5, 20.2; LC-MS (method: 0.5 min 95% H₂O/5% MeCN→5 min 0%H₂O/100% MeCN, rt=1.98 min. MS calc'd for C₂₅H₂₈N₆O₅P (MH⁺): 523.2.Found 523.2.

For 133-2: ¹H NMR (300 MHz, CD₃OD) δ 8.15 (1H, dd), 7.72 (1H, s), 7.67(1H, m), 7.39 (2H, m), 7.28 (1H, m), 6.44 (1H, dd), 5.40 (2H, s),4.23-3.90 (6H, m), 1.42 (6H, m), 1.27 (3H, t), 1.18 (3H, t); ³¹P NMR(121 MHz, CD₃OD) δ 19.7; LC-MS (method: 0.5 min 95% H₂O/5% MeCN 5 min 0%H₂O/100% MeCN, rt=1.86 min. MS calc'd for C₂₄H₃₃N₇O₆P (MH⁺): 546.2.Found 546.2.

Example 287 Pro-Drug Cleavage Assays Isolation of PBMC Extracts:

Fresh human PBMCs were obtained from patients undergoing leukophoresis;cells were shipped in plasma and processed within 26 h of draw.Purification was achieved using the Ficoll-Paque method: PBMC cells wereharvested by centrifugation at 1200×g for 5 minutes and washed threetimes by re-suspension in RBC lysis buffer (155 mM NH₄Cl, 0.1 mM EDTA,10 mM KHCO₃). Washed cells were suspended in lysis buffer (0.2×10⁹ cellsin 1 ml of 10 mM Tris, pH 7.4, 150 mM NaCl, 20 mM CaCl₂, 1 mM DTT and 1%NP40) and incubated on ice for 20 minutes. The PBMC crude extract wascentrifuged at 1000×g for 30 min to remove unlysed cells and thesupernatant at 100,000 X g for 1 h. The 100,000×g supernatant (PBMCExtract: P0) was harvested, snap frozen in liquid nitrogen and stored at−70° C.

Protocol for Measurement of Cleavage of Prodrugs by PBMC Extracts:

Reaction mixtures contained 25 mM MesNa (pH 6.5), 100 mM NaCl, 1 mM DTT,0.1% NP-40, 30 μM substrate, and varying amounts of enzyme in a finalvolume of 100 μl. The enzymatic reaction is performed at 37° C. for10-120 minutes and stopped at 3-4 individual time points by adding 180μl of ice cold methanol. Samples are incubated @ −20° C. for 30 min, andcentrifuged 13,000 RPM for 30 min (@ 4° C.). The supernatant istransferred to a 96 well plate and evaporated under vacuum using aspeedvac. The precipitate is dissolved in 100 μl of 20 mM CH₃COONH₄+5%AcCN. The disappearance of pro-drug is measured by HPLC, monitoring at260 nm. The specific activity of the PBMC Extract against the prodrugstested is defined as: v (cleavage rate)/μg protein=pmoles/min/μg.

Results Human PBMC extract specific Compound activity (pmol/min/μg)130-1 3.48 130-2 0.65 133-1 4.9 133-2 0.38

Example 288

Representative compounds of the invention having the following formulaecan be prepared as described herein.

For example, three regions of mycophenolate mofetil can be utilized forthe attachment of the phosphonate prodrug as demonstrated by compoundsD, E, and G shown above. Also, the carboxylic acid can be replaced witha phosphonic acid as in compound F.

Example 288A

Representative compounds of the invention can be prepared as illustratedabove. The morpholino ethyl moiety can serve as a prodrug functionalityto improve bioavailability and can be replaced with the phosphonateprodrug handle as shown above. Mycophenolic acid is commerciallyavailable, e.g., from Sigma Chemical Company, St. Louis, Mo. Activationof the carboxylic acid 288.1 in the presence of the free phenol,followed by addition of an alcohol carrying the phosphonate group,results in the formation of the desired product 288.3 (U.S. Pat. No.4,786,637). A specific compound of the invention can be prepared asfollows.

Mycophenolic acid 288.1 is dissolved in dichloromethane. Thionylchloride is added followed by a catalytic amount of DMF. The reactionmixture is stirred at room temperature for 3 hours, after which thevolatile components are removed under vacuum. The phosphonate-alcohol isdissolved in dichloromethane and chilled to about 4° C. on an ice bath.The mycophenolic acid chloride 288.2 is dissolved in dichloromethane andadded to the chilled solution. After stirring for 90 minutes at about 4°C., the reaction mixture is washed with water and then with aqueoussodium bicarbonate. The organic solution is dried and evaporated toyield the phosphonate 288.4.

Example 289

Representative compounds of the invention can be prepared as illustratedabove. The C-4 phenol position provides a reactive handle for furtheranalogs as illustrated above. Once the carboxylic acid of 289.1 isblocked by morpholino ethyl, such as in compound 289.2 the phenol can bealkylated under basic conditions. Bases such as pyridine, potassiumcarbonate, or triethylamine are utilized. Leaving groups such astrifluoromethylsulfonate, mesylate, bromide, or iodide are attached tothe phosphonate prodrug subunit and reacted, in the presence of base,with compound 289.2. Compound 289.3 can either be used directly, or inthe form of a salt, compound 289.4. Among the large number of salts thatcan be prepared, chloride and bisulfate salts are one particularembodiment of the invention. A specific compound of the invention can beprepared as follows.

Compound 289.5 is prepared similar to compound 289.2 (described inExample 288). A solution of morpholino ethanol in dichloromethane iscooled to about 4° C. The mycophenolic acid chloride 289.5 is dissolvedin dichloromethane and added to the cooled solution. Stirring thissolution for about 90 minutes gives compound 289.2. The reaction mixtureis washed with water and dried with sodium sulfate. Removal of thesolvent provides isolated compound 289.2. Alkylation at the phenolicposition of 289.2 is achieved by suspending the compound in pyridine.Triflate 289.6 is added to the solution and the mixture is stirred atroom temperature for about 90 minutes. The reaction mixture is pouredinto water and the product is extracted with ethyl acetate. Removal ofthe organic layer provides compound 289.7. Hydrochloride salt of 289.7can optionally be prepared. Compound 289.7 is dissolved in isopropanoland the solution is added to a mixture of hydrogen chloride inisopropanol. The hydrochloride salt 289.8 is collected by filtration anddried under vacuum.

Example 290

Representative compounds of the invention can be prepared as illustratedabove. The carboxylic acid of mycophenolic acid can be replaced with aphosphonic acid that may also serves as a prodrug handle. In order toremove the carboxylic acid containing side chain, the acid chloride290.5 (prepared in Example 289) is converted to ester 290.1. Protectionof the phenol with a silyl group, followed by dihydroxylation andcleavage of the diol generates aldehyde 290.3 (Pankiewicz, et al., J.Med. Chem., 2002, 45, 703), (Patterson et al., U.S. Pat. No. 5,444,072).A Wittig reaction with ylide 290.4 carrying an appropriately protectedphosphonate provides the desired compound 290.5. Final deprotectionyields compound 290.6. A specific compound of the invention can beprepared as follows.

Mycophenolate ester 290.8 can simply be prepared by stirring the acidchloride 290.7 with MeOH. Then, the phenol position of mycophenolateester is protected by a silyl group such as TBS to provide compound290.9. Once the phenol position is protected, dihydroxylation usingosmium tetraoxide followed by periodinate cleavage provides aldehyde290.10. Aldehyde 290.10 and excess of the ylide 290.11 are heated inbenzene at reflux for about 24 hours. The reaction mixture isconcentrated and the residue is purified by column chromatography toprovide olefin 290.12 (Pankiewics et al., J. Med. Chem., 2002, 45, 703).A final deprotection using HF-pyridine yields the final product 290.13.

Example 291

Representative compounds of the invention can be prepared as illustratedabove. Another attachment point of the compound can be unmasked afterdemethylation of mycophenolate ester 291.2 as illustrated above. Forthis purpose, the 4-OH needs to be masked with a protecting group (P)such as a silyl group. Once the 6-MeO is demethylated and alkylated, theprotecting group at position 4 is removed to reveal the final product291.4. The morphonyl ethanol group is installed early and carriedthrough the alkylation steps. A different protecting group may beinstalled initially and removed later. In such the latter type ofsynthesis, the last step is the formation of the morpholinoethyl esterprodrug. A specific compound of the invention can be prepared asdescribed below.

Phenol 291.5 is protected with TBS group in CH₂Cl₂ using imidazole asbase to yield 291.6. Demethylation is performed using thiolatenucleophiles to generate compound 291.7. A variety of other methods arealso available in literature as described in Protective Groups inOrganic Synthesis by Greene and Wuts. Alklation of the 6-OH using atriflate of the phosphonate proceeds well using K₂CO₃ or TEA to provide291.8. Final deprotection to remove the TBS group provides product291.9.

Example 292

Representative compounds of the invention can be prepared as illustratedabove.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diisopropyl ester

A mixture of7-hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one1A (50 mg, 0.18 mmol, Pankiewicz et al., J. Med. Chem., 45, 703),diisopropyl bromomethylphosphonate (93 mg, 0.36 mmol) and lithiumt-butoxide (1M in THF, 0.54 mL) in DMF (3 mL) was heated at 70° C. for 5hours. The reaction was quenched with 1N HCl. The mixture was pouredinto 5% aqueous lithium chloride, extracted with ethyl acetate, andconcentrated. The residue was purified by chromatography on silica gel,affording[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diisopropyl ester 1B (25 mg, 32%); ¹H NMR (300 MHz, CDCl₃) δ1.25(m, 12H), 1.79 (s, 3H), 2.05 (s, 3H), 3.37 (d, J=6.6 Hz, 2H), 3.58 (d,2H), 3.77 (s, 3H), 3.97 (m, 2H), 4.68 (m, 2H), 5.19 (s, 2H), 5.45 (t,J=6.6 Hz, 1H), 7.83 (s, 1H) ppm.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid and[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monoisopropyl ester

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diisopropyl ester 1B (25 mg, 0.055 mmol) and 2,6-lutidine (0.18 mL,1.65 mmol) in acetonitrile was added trimethylsilyl bromide (0.126 mL,1.1 mmol) at 0° C. The mixture was allowed to warm to room temperatureand stirred for 4 hours. The reaction was quenched with methanol at 0°C., and the resulting mixture was concentrated. The residue was purifiedby preparative reverse-phase HPLC to afford, after removal of thesolvent,[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid 1C as an oil (17 mg, 83%); ¹H NMR (300 MHz, CD₃OD) δ 1.81 (s, 3H),2.06 (s, 3H), 3.40 (d, J=6.6 Hz, 2H), 3.50 (d, 2H), 3.77 (s, 3H), 3.97(s, 2H), 5.20 (s, 2H), 5.47 (t, J=6.6 Hz, 1H) and[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monoisopropyl ester 1D as an oil (2 mg, 7%); ¹H NMR (300 MHz,CD₃OD) δ 1.23 (d, 6H), 1.81 (s, 3H), 2.08 (s, 3H), 3.40 (d, J=6.6 Hz,2H), 3.50 (d, 2H), 3.77 (s, 3H), 3.90 (s, 2H), 4.50 (m, 1H), 5.20 (s,2H), 5.47 (t, J=6.6 Hz, 1H) ppm.

Example 293

Representative compounds of the invention can be prepared as illustratedbelow.

[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid dimethyl ester

To a solution of tetramethylmethylene diphosphonate (102 mg, 0.44 mmol)in THF (2.5 mL) was added a THF solution of sodiumbis(trimethyl-silyl)amide (1.0 M, 0.44 mL). After stirring for 30minutes, a solution of4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enal2A (30 mg, 0.11 mmol, Pankiewicz et al., J. Med. Chem., 45, 703) in THF(2.5 mL) was added, and stirring was continued for an additional 15minutes. The reaction was quenched with saturated aqueous ammoniumchloride. The mixture was extracted with ethyl acetate. Afterevaporation of solvent, the residue was purified by chromatography onsilica gel eluting with ethyl acetate (50% to 100%)/hexanes, affording[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid dimethyl ester 2B (30 mg, 71%) as an oil; ¹H NMR (300 MHz, CDCl₃) δ1.80 (s, 3H), 2.04 (s, 3H), 3.45 (d, J=6.6 Hz, 2H), 3.76 (s, 3H), 3.88(d, 6H), 5.20 (s, 3H), 5.55 (m, 1H), 5.95 (m, 1H), 7.05 (m, 1H), 7.65(s, 1H) ppm.

[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid

To a solution of[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid dimethyl ester 2B (22 mg, 0.057 mmol) and 2,6-lutidine (0.22 mL,1.71 mmol) in acetonitrile was added trimethylsilyl bromide (0.183 mL,1.71 mmol) at 0° C. The mixture was allowed to warm to room temperatureand stirred for 1 hour. The reaction was quenched with methanol at 0°C., and the resulting mixture was concentrated. The residue was purifiedby preparative reverse-phase HPLC to afford, after removal of thesolvent,[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonicacid 2C as a solid (13 mg, 65%); ¹H NMR (300 MHz, CD₃OD) δ 1.91 (s, 3H),2.10 (s, 3H), 3.55 (d, J=6.6 Hz, 2H), 3.75 (s, 3H), 5.2 (s, 2H), 5.6-5.8(m, 2H), 6.9 (m, 1H) ppm.

Example 294

Representative compounds of the invention can be prepared as illustratedbelow.

6-(4-Bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one

Polymer-supported triphenylphosphine (3 mmol/g, 0.5 g) was soaked indichloromethane (10 mL) for 1 hour7-Hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one1A (100 mg, 0.36 mmol) and carbon tetrabromide (143 mg, 0.43 mmol) weresequentially added and the mixture was shaken for 1 hour at roomtemperature. More carbon tetrabromide (143 mg, 0.43 mmol) was added andthe mixture was shaken further for 1 hour. The mixture was filtered andthe filtrate was concentrated. The residue was chromatographed on silicagel (0% to 60% ethyl acetate/hexanes) to afford6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one3B as an oil (52 mg, 42%); ¹H NMR (300 MHz, CDCl₃) δ 1.95 (s, 3H), 2.16(s, 3H), 3.44 (d, J=7.2 Hz, 2H), 3.78 (s, 3H), 3.98 (s, 2H), 5.21 (s,2H), 5.68 (t, J=7.2 Hz, 1H), 7.71 (brs, 1H) ppm.

[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid diethyl ester

n-Butyl lithium (1.6 M in hexanes, 1 mL) was added to an equal volume ofTHF at −20° C. A solution of diethyl methylphosphonate (220 mg, 1.45mmol) in THF (1 mL) was then added dropwise and the solution was stirredfor 30 minutes. After cooling at 60° C., the solution was transferredvia a cannula to a vial containing copper (I) iodide (276 mg, 1.45mmol), and the resulting mixture was stirred for 1 hour at −30° C. Asolution of6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one3B (50 mg, 0.15 mmol) in THF (1 mL) was added and the mixture wasallowed to warm to 0° C. for 2 hours before saturated aqueous ammoniumchloride was added. The reaction mixture was acidified with 2 N HCl andextracted with ethyl acetate. The ethyl acetate extract was concentratedand the residue was chromatographed on silica gel (40% to 100% ethylacetate/hexanes), affording[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid diethyl ester 3C as an oil (27 mg, contaminated with the startingdiethyl methylphosphonate); ¹H NMR (300 MHz, CDCl₃) δ 1.32 (m, 6H),1.8-1.9 (m, 5H), 2.18 (s, 3H), 2.25 (m, 2H), 3.42 (d, J=7.2 Hz, 2H),3.78 (s, 3H), 4.15 (m, 4H), 5.21 (s, 2H), 5.24 (t, J=7.2 Hz, 1H), 7.65(s, 1H) ppm.

[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid monoethyl ester

A mixture of[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid diethyl ester 3C (27 mg, 0.066 mmol), LiOH (200 mg), MeOH (3 mL)and water (1 mL) was stirred at 70° C. for 4 hours. After cooling, thereaction solution was acidified with 2 N HCl, mixed with brine, andextracted with ethyl acetate/acetonitrile. The organic extract wasconcentrated and the residue was purified by preparative reverse-phaseHPLC (acetonitrile and 0.1% aqueous CF₃COOH), affording[5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid monoethyl ester 3D (7 mg, 28%); ¹H NMR (300 MHz, CD₃OD) δ 1.28 (t,J=6.9 Hz, 3H), 1.7-1.9 (m, 5H), 2.20 (s, 3H), 2.2-2.3 (m, 2H), 3.41 (d,J=6.6 Hz, 2H), 3.80 (s, 3H), 4.02 (m, 2H), 5.2-5.3 (m, 3H) ppm.

[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid

To a solution of{5-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonicacid diethyl ester (20 mg, 0.039 mmol) in DMF (0.5 mL) and DCM (0.5 mL)was added TMSBr (50.5 μL, 0.39 mmol) followed by 2,6-lutidine (45.3 μL,0.39 mmol). The reaction was allowed to proceed for one hour when it wascomplete, as judged by LCMS. The reaction mixture was quenched with MeOHand concentrated to dryness. The residue was purified by preparativereverse-phase HPLC. The fraction containing the desired product wasconcentrated and treated with 10% TFA/DCM for 5 minutes. Afterconcentration, the residue was purified by preparative reverse-phaseHPLC to provide 7 mg (50%) of[5-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid as a solid. ¹H NMR (300 MHz, CD₃OD) δ 1.66-1.78 (m, 5H), 2.10 (s,3H), 2.16-2.22 (m, 2H), 3.34 (d, J=7.2 Hz, 2H), 3.72 (s, 3H), 5.16 (s,2H), 5.20 (t, J=7.2 Hz, 1H) ppm; ³¹P (121.4 MHz, CD₃OD) δ 31.57 ppm; MS(m/z) 355 [M−H]⁻, 357 [M+H]⁺.

Example 295

Representative compounds of the invention can be prepared as illustratedbelow.

2-(4-Bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester

To a cooled (−78° C.) solution of mycophenolic acid methyl ester 4A (138mg, 0.41 mmol) in THF (2.5 mL) was added a THF solution of sodiumbis(trimethysilyl)amide (1.0 M, 0.98 mL). After stirring for 30 minutes,a solution of 1,4-dibromo-2-butene (950 mg, 4.1 mmol) in THF (2.5 mL)was added and stirring was continued for 10 minutes. The resultingmixture was warmed to −30° C. and stored at this temperature for 16hours. The reaction was quenched with saturated aqueous ammoniumchloride. The mixture was extracted with ethyl acetate to give, afterevaporation of the solvent, a residue that was purified bychromatography on silica gel eluting with ethyl acetate (0% to40%)/hexanes, affording2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester 4B (150 mg, 78%) as an oil; ¹H NMR (300 MHz, CDCl₃) δ1.75 (s, 3H), 2.0-2.4 (m, 8H), 2.62 (m, 1H), 3.37 (d, J=6.6 Hz, 2H),3.58 (s, 3H), 3.76 (s, 3H), 3.88 (d, J=4.8 Hz, 2H), 5.1-5.3 (m, 3H),5.67 (brs, 2H), 7.67 (s, 1H) ppm.

2-[4-(Diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester

A solution of2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester 4B (140 mg, 0.30 mmol) and triethylphosphite (600 mg,3.6 mmol) in toluene (30 mL) was stirred at reflux for 20 hours. Themixture was concentrated and chromatographed on silica gel eluting withethyl acetate (60% to 100%)/hexanes, affording2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester 4C as an oil (70 mg, 43%); ¹H NMR (300 MHz, CDCl₃) δ1.27 (m, 6H), 1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J=6.6 Hz), 3.52(s, 3H), 3.75 (s, 3H), 4.08 (m, 4H), 5.20 m, 3H), 5.45 (m, 2H) ppm.

2-[4-(Diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

A mixture of2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester 4C (33 mg, 0.063 mmol) and lithium hydroxide (44 mg)in a mixture of THF (6 mL) and water (1 mL) was stirred at roomtemperature for 6 hours. The organic solvent was removed and the residuewas partitioned between ethyl acetate and 5% aqueous sodium bicarbonate.The aqueous layer was acidified with 2 N HCl and extracted with ethylacetate. The ethyl acetate extract was concentrated, affording2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid 4D as an oil (30 mg, 100%); ¹H NMR (300 MHz, CDCl₃) δ 1.27 (m, 6H),1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J=6.6 Hz), 3.75 (s, 3H), 4.08(m, 4H), 5.19 (s, 2H), 5.25 (m, 1H), 5.44 (m, 1H), 5.55 (m, 1H), 5.45(m, 2H) ppm.

2-[4-(Ethoxy-hydroxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid

A mixture of2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester 4C (25 mg, 0.048 mmol) and lithium hydroxide (200 mg)in a mixture of methanol (3 mL) and water (1 mL) was stirred at 70° C.for 2 hours. The organic solvent was evaporated and the residueacidified with 2N HCl and extracted with ethyl acetate/acetonitrile. Theorganic extract was concentrated, and the residue was purified bypreparative reverse-phase HPLC (acetonitrile and 0.1% aqueous CF₃COOH),affording2-[4-(ethoxy-hydroxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid 4E as an oil (15 mg, 89%); ¹H NMR (300 MHz, CD₃OD) δ 1.25 (t, J=6.9Hz, 3H), 1.81 (s, 3H), 2.1-2.6 (m, 8H), 3.40 (d, J=6.6 Hz, 2H), 3.77 (s,3H), 3.97 (m, 2H), 5.1-5.3 (m, 3H), 5.67 (brs, 2H) ppm.

2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester

Under a N₂ atmosphere, a solution of2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester (490 mg, 1.05 mmol) in trimethylphosphite (2.5 mL,21.1 mmol) was heated at 120° C. for 1 hour. The reaction was allowed tocool to room temperature. The reaction mixture was worked up by removalof the solvent in vacuo followed by chromatography using EtOAc-hexanesto provide 460 mg (88%) of the product as an oil. ¹H NMR (300 MHz,CDCl₃) δ 1.77 (s, 3H), 2.081-2.31 (m, 4H), 2.15 (s, 3H), 2.52 (d, 1H,J=22 Hz), 2.54 (d, 1H, J=22 Hz), 2.55-2.63 (m, 1H), 3.36 (d, 2H, J=7Hz), 3.57 (s, 3H), 3.72 (d, 6H, J=11 Hz), 3.76 (s, 3H), 5.20 (s, 2H),5.20-5.26 (m, 1H), 5.36-5.56 (m, 2H), 7.69 (s, 1H) ppm; ³¹P (121.4 MHz,CDCl₃) δ 30.1 ppm; MS (m/z) 497.2 [M+H]⁺, 519.2 [M+Na]⁺.

2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester (460 mg, 0.927 mmol) in a solution of 1:1:2 of H₂O,MeOH, THF (8 mL) was stirred with LiOH.H₂O (78 mg, 1.86 mmol) at ambienttemperature for 12 hours. A second batch of LiOH.H₂O (40 mg, 0.952 mmol)was added. The reaction mixture was stirred at room temperature foranother 16 hours, after which no further progress was observed. Thereaction was quenched by addition of a saturated aqueous solution ofNH₄Cl. The organic layer was removed in vacuo and the product wasextracted with EtOAc from the aqueous layer, which had been acidified byaddition of 5 drops of 2 N HCl. The product was further purified bychromatography to provide the desired product. ¹H NMR (300 MHz, CDCl₃) δ1.79 (s, 3H), 2.08-2.38 (m, 4H), 2.15 (s, 3H), 2.53 (d, 1H, J=22 Hz),2.60 (d, 1H, J=22 Hz), 2.57-2.64 (m, 1H), 3.38 (d, 2H, J=7 Hz), 3.72 (d,6H, J=11 Hz) 3.76 (s, 3H), 5.20 (s, 2H), 5.27 (t, 1H, J=6 Hz), 5.36-5.63(m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 30.5 ppm; MS (m/z) 481.2 [M−H]⁻.

2-[4-(2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

To a solution of2-[4-(dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid (25 mg, 0.052 mmol) in acetonitrile (2 mL) was added 2,6-lutidine(60 μL, 0.52 mmol) and TMSBr (67 μL, 0.52 mmol). The reaction wasallowed to proceed for 45 minutes when it was completed as judged byLCMS. The reaction mixture was concentrated under reduced pressure andquenched with an aqueous NaOH solution (1 mL). The product was purifiedby RP HPLC (using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA) to provide 14.2 mg (60%) of the product as asolid. ¹H NMR (300 MHz, CD₃OD) δ 1.81 (s, 3H), 2.081-2.31 (m, 4H), 2.16(s, 3H), 2.45 (d, 1H, J=22 Hz), 2.47 (d, 1H, J=22 Hz), 2.55-2.63 (m,1H), 3.38 (d, 2H, J=7 Hz), 3.77 (s, 3H), 5.25 (s, 2H), 5.20-5.36 (m,1H), 5.36-5.56 (m, 2H) ppm; ³¹P (121.4 MHz, CD₃OD) δ 25.4 ppm; MS (m/z)453 [M−H]⁻.

2-[4-(Dimethoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A solution of2-[4-(dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid (160 mg, 0.332 mmol) and trimethylsilylethanol (160 mg, 1.36 mmol)in THF (8.00 mL) was stirred with triphenylphosphine (345 mg, 1.33mmol). To this solution was added diethyl azodicarboxylate (230 μL, 1.33mmol) at 0° C. The mixture was allowed to warm to room temperature andstirred for 16 hours. Additional triphenylphosphine (180 mg, 0.692mmol), trimethylsilylethanol (160 mg, 1.36 mmol), and diethylazodicarboxylate (115 μL, 0.665 mmol) were added and the reactionmixture was stirred for another 1 day at room temperature. The reactionwas worked up by removing the solvents in vacuo and purifying theresidue by silica gel chromatography to provide 192 mg (85%) of theproduct as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 0.05 (s,9H), 0.93-0.96 (m, 2H), 1.20-1.29 (m, 2H), 1.78 (s, 3H), 2.01-2.32 (m,4H), 2.17 (s, 3H), 2.51 (d, 1H, J=22 Hz), 2.58 (d, 1H, J=22 Hz),2.50-2.60 (m, 1H), 3.37 (d, 2H, J=7 Hz), 3.72 (d, 6H, J=11 Hz), 3.76 (s,3H), 4.08 (appt t, 2H, J=8 Hz), 4.30 (appt t, 2H, J=8 Hz), 5.12 (s, 2H),5.15-5.25 (m, 1H), 5.36-5.63 (m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 29.3ppm; MS (m/z) 705.3 [M+Na]⁺.

2-[4-(Hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A mixture of2-[4-(dimethoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (184 mg, 0.270 mmol) intert-butylamine (2.8 mL, 27 mmol) was heated at 60° C. for 24 hours. Thesolution was allowed to cool to room temperature and concentrated. Theresidue was purified by silica gel column chromatography usingMeOH/CH₂Cl₂ (0-30%) to provide 75 mg of the product as a clear oil. ¹HNMR (300 MHz, CDCl₃) δ 0.01 (s, 9H), 0.04 (s, 9H), 0.89 (appt t, 2H, J=9Hz), 1.23 (appt t, 2H, J=9 Hz), 1.77 (s, 3H), 2.01-2.31 (m, 4H), 2.17(s, 3H), 2.36 (d, 1H, J=22 Hz), 2.38 (d, 1H, J=22 Hz), 2.52 (septet, 1H,J=9 Hz), 3.39 (d, 2H, J=7 Hz), 3.51 (d, 3H, J=11 Hz), 4.01-4.08 (m, 2H),4.30 (dd, 2H, J=8, 9 Hz), 5.11 (s, 2H), 5.19 (br t, 1H, J=6 Hz),5.33-5.56 (m, 2H), 8.49 (br s, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 22.1ppm; MS (m/z) 667.4 [M+Na]⁺.

2-{4-[(1-Ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester

A solution of2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (67 mg, 0.10 mmol) and PyBOP (234mg, 0.450 mmol) in DMF (1.5 mL) was stirred with ethyl (S)-(−)-lactate(53 mg, 0.45 mmol) and DIEA (174 μL, 1.00 mmol) at ambient temperaturefor 1 hour, when complete consumption of the starting materials wasobserved. The reaction was worked up by addition of saturated aqueoussodium chloride and ethyl acetate. The organic layer was separated andwashed with 5% aqueous solution of lithium chloride. The organic layerwas dried in vacuo and the residue was purified by silica gelchromatography using MeOH—CH₂Cl₂ (0-20%) to provide 57 mg (74%) of thedesired product as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 0.02 (s, 9H),0.05 (s, 9H), 0.88-0.94 (m, 2H), 1.20-1.30 (m, 2H), 1.29 (t, 3H, J=7Hz), 1.45 (d, 3H, J=7 Hz), 1.78 (s, 3H), 2.01-2.31 (m, 4H), 2.17 (s,3H), 2.50-2.58 (m, 1H), 2.65 (d, 1H, J=22 Hz), 2.67 (d, 1H, J=22 Hz),3.39 (d, 2H, J=7 Hz), 3.69 and 3.77 (d, 3H, J=11 Hz), 3.76 (s, 3H), 4.07(appt t, 2H, J=7 Hz), 4.20 (dq, 2H, J=3, 7 Hz), 4.29 (appt t, 2H, J=9Hz), 4.85-4.99 (m, 1H), 5.12 (s, 2H), 5.19 (br t, 1H, J=6 Hz), 5.33-5.61(m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 28.9, 29.9 ppm; MS (m/z) 791.4[M+Na]⁺.

2-{4-[(1-Ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

A solution of2-{4-[(1-ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (14 mg, 0.018 mmol) in THF (1 mL)was stirred with a 1M solution of TBAF in THF (55 μL, 0.055 mmol) for 1hour. The reaction mixture was concentrated, acidified with 1N HCl andextracted with EtOAc. The organic layer was washed with brine and dried.The product was purified by silica gel column chromatography EtOH-EtOAc(0-10%). Further purification was performed by dissolving the product inCH₂Cl₂ and passing the compound through a 13 mm Acrodisc syringe filterwith a 0.45 μm Nylon membrane to provide 8 mg (77%) of the product. ¹HNMR (300 MHz, CDCl₃) δ 0.92 (t, 3H, J=7 Hz), 1.30 (d, 3H, J=8 Hz), 1.79(s, 3H), 2.10-2.39 (m, 4H), 2.15 (s, 3H), 2.53 (d, 1H, J=8 Hz), 2.65 (d,1H, J=22 Hz), 2.68 (d, 1H, J=22 Hz), 3.38 (d, 2H, J=7 Hz), 3.70 and 3.74(d, 3H, J=11 Hz), 3.76 (s, 3H), 4.07 (m, 2H), 4.96 (dq, 1H, J=7 Hz),5.20 (s, 2H), 5.27 (br t, 1H, J=7 Hz), 5.33-5.55 (m, 2H), 7.51-7.56 (m,1H), 7.68-7.74 (m, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 29.0, 30.1 ppm; MS(m/z) 569.2 [M+H]⁺, 591.3 [M+Na]⁺.

2-{4-[(1-Carboxy-ethoxy)-hydroxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A solution of2-{4-[(1-ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanylethyl ester (12 mg, 0.016 mmol) intert-butylamine (1 mL, 9.6 mmol) was heated at 65° C. for 16 hours. Thesolution was allowed to cool to room temperature and concentrated toprovide the crude product as an oil. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s,9H), 0.04 (s, 9H), 0.86-0.98 (m, 2H), 1.22-1.33 (m, 2H), 1.50 (d, 3H,J=7 Hz), 1.78 (s, 3H), 2.05-2.30 (m, 4H), 2.10 (s, 3H), 2.48-2.63 (m,3H), 3.40 (d, 2H, J=7 Hz), 3.76 (s, 3H), 4.08 (appt t, 2H, J=9 Hz),4.25-4.33 (m, 2H), 4.75-4.84 (m, 1H), 5.13 (s, 2H), 5.15-5.23 (m, 1H),5.33-5.55 (m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 28.9 ppm; MS (m/z) 725.3[M−H]⁻.

2-{4-[(1-Carboxy-ethoxy)-hydroxy-phosphoryl]-but-2-enyl}-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

A solution of crude2-{4-[(1-carboxy-ethoxy)-hydroxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (AC-2101-59) and tetrabutylammoniumfluoride in THF (1M, 54 μL, 0.054 mmol) was stirred with THF (1 mL) for2 hours at ambient temperature, when more tetrabutylammonium fluoride inTHF (54 μL, 0.054 mmol) was added. The reaction was stirred for anadditional 16 hours, by which time the reaction was complete. Thereaction mixture was concentrated in vacuo and the product was purifiedby RP HPLC using a Phenomenex Synergi 5μ Hydro RP 80A column (50×21.2mm) with eluents of H₂O, 0.1% TFA-CH₃CN, 0.1% TFA to provide the product(8.0 mg) as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 1.51 (d, 3H, J=7 Hz),1.79 (s, 3H), 2.05-2.40 (m, 4H), 2.11 (s, 3H), 2.49-2.71 (m, 3H), 3.38(d, 2H, J=6 Hz), 3.76 (s, 3H), 4.85 (br s, 1H), 5.20 (s, 2H), 5.21-5.30(m, 1H), 5.33-5.63 (m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 27.7 ppm; MS(m/z) 525.2 [M−H]⁻.

2-{4-[(1-Ethoxycarbonyl-ethylamine)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester

A solution of2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (20 mg, 0.030 mmol), PyBOP (62.4 mg,0.120 mmol) in DMF (1.0 mL) was stirred with L-alanine ethyl esterhydrochloride (18 mg, 0.12 mmol) and DIEA (26 μL, 0.15 mmol) at ambienttemperature for 1 hour, when complete consumption of the startingmaterials was observed. The reaction was worked up by addition of wateruntil the reaction solution became cloudy. DMF was added dropwise untilthe mixture became clear again. The reaction mixture was filteredthrough Acrodisc (13 mm syringe filter with a 0.45 μm Nylon membrane)and purified by RP HPLC using a Phenomenex Synergi 5μ Hydro RP 80Acolumn (50×21.2 mm), eluting with water and acetonitrile. The fractionscontaining the product were pooled together and concentrated in vacuo toremove the acetonitrile. The remaining solution was saturated withsodium chloride and extracted with EtOAc and acetonitrile to provide 7.2mg of the product. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 0.05 (s, 9H),0.923 (appt t, 2H, J=8 Hz), 1.18-1.31 (m, 5H), 1.41 (t, 3H, J=7 Hz),1.78 (s, 3H), 2.03-2.36 (m, 4H), 2.18 (s, 3H), 2.43-2.63 (m, 3H),3.10-3.30 (m, 1H), 3.40 (d, 2H, J=7 Hz), 3.62 and 3.65 (d, 3H, J=11 Hz),3.76 (s, 3H), 4.03-4.12 (m, 2H), 4.20 (dq, 2H, J=2, 7 Hz), 4.29 (appt t,2H, J=8 Hz), 5.12 (s, 2H), 5.18-5.28 (m, 1H), 5.33-5.67 (m, 2H) ppm; ³¹P(121.4 MHz, CDCl₃) δ 30.4, 31.2 ppm; MS (m/z) 790.4 [M+Na]⁺.

2-{4-[(1-Ethoxycarbonyl-ethylamine)-methoxy-phosphoryl]-but-2-enyl}-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid

To a solution of2-{4-[(1-ethoxycarbonyl-ethylamine)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanyl-ethyl ester (7.2 mg, 9.38 mmol) in THF (1 mL)was added TBAF (40 μL, 1M solution in THF) at room temperature. Thereaction mixture was stirred for 20 minutes, when the starting materialwas completely converted to the desired product as judged by LCMS. Thereaction mixture was dried in vacuo and re-dissolved in DMF. The productwas purified by RP HPLC using a Phenomenex Synergi 5μ Hydro RP 80Acolumn (50×21.2 mm) with eluents of H₂O—CH₃CN. The fractions containingthe desired product were pooled and further purified on Dowex 50WX8-400packed on a 4.5 cm×2 cm column to elute the sodium salt at H₂O— MeOH(1:1), providing 3.2 mg of the desired product. ¹H NMR (300 MHz, CD₃OD)δ 1.26 (dd, 3H, J=4, 7 Hz), 1.37 (t, 3H, J=8 Hz), 1.80 (s, 3H),2.00-2.22 (m, 4H), 2.10 (s, 3H), 2.25-2.60 (m, 3H), 3.37 (d, 2H, J=7Hz), 3.60 and 3.65 (d, 3H, J=11 Hz), 3.74 (s, 3H), 3.83-3.96 (m, 1H),4.18 (q, 2H, J=8 Hz), 5.15 (s, 2H), 5.25-5.42 (m, 2H), 5.55-5.69 (m, 1H)ppm; ³¹P (121.4 MHz, CD₃OD) δ 33.8, 34.2 ppm; MS (m/z) 568.2 [M+H]⁺,590.3 [M+Na]⁺.

6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-4-methyl-hex-4-enoicacid

To a solution of2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid 2-trimethylsilanylethyl ester (11 mg, 0.016 mmol) in THF (1 mL) wasadded TBAF (50 μL, 1M solution in THF) at room temperature. The solutionwas stirred for 16 hours and concentrated. The solution was dried underreduced pressure and re-suspended in DMF (0.8 mL) and water (0.25 mL).The solution was filtered through Acrodisc (13 mm syringe filter with a0.45 μm Nylon membrane) and purified by RP HPLC using a PhenomenexSynergi 5μ Hydro RP 80A column (50×21.2 mm) with eluents of H₂O, 0.1%TFA-CH₃CN, 0.1% TFA. The product from the column was subjected to ionexchange chromatography (Sodium salt form of Dowex 50WX8-400) using a2×4.5 cm column eluting with H₂O-MeOH (1:1) to provide 7.5 mg of thedesired product as an oil. ¹H NMR (300 MHz, CDCl₃) δ 1.80 (s, 3H),2.01-2.29 (m, 5H), 2.11 (s, 3H), 2.35 (d, 2H, J=22 Hz), 3.38 (d, 2H, J=7Hz), 3.53 (d, 3H, J=11 Hz), 3.75 (s, 3H), 5.19 (s, 2H), 5.26 (t, 1H, J=6Hz), 5.43-5.54 (m, 2H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 23.5 ppm; MS (m/z)469.2 [M+H]⁺, 491.3 [M+Na]⁺.

6-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester

To a solution of6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoicacid methyl ester (222 mg, 0.66 mmol), triphenylphosphine (260 mg, 0.996mmol), and diethyl azodicarboxylate (173 mg, 0.996 mmol) in THF (3 mL)at 0° C. was added a solution of 2-trimethylsilylethanol (142 μL, 0.996mmol) in THF (3 mL). The resulting yellow solution was allowed to warmto room temperature and stirred overnight. The reaction was concentratedto dryness and ether and hexanes were added. Triphenylphosphine oxidewas removed by filtration and the filtrate was concentrated and purifiedby silica gel chromatography to provide 248 mg of the desired product asa colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 1.18-1.30 (m,2H), 1.81 (s, 3H), 2.18 (s, 3H), 2.25-2.33 (m, 2H), 2.37-2.45 (m, 2H),3.42 (d, 2H, J=7 Hz), 3.62 (s, 3H), 3.77 (s, 3H), 4.25-4.35 (m, 2H),5.13 (s, 2H), 5.12-5.22 (m, 1H) ppm.

[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde

A solution of6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester (618 mg, 1.42 mmol) in MeOH (10 mL), CH₂Cl₂ (10 mL)and pyridine (50 μL, 0.618 mmol) was cooled to −70° C. using a dryice/acetone bath according to the procedure of Smith, D. B. et al., J.Org. Chem., 1996, 61, 6, 2236. A stream of ozone was bubbled through thereaction via a gas dispersion tube until the reaction became blue incolor (15 minutes). The ozone line was replaced with a stream ofnitrogen and bubbling continued for another 15 minutes, by which timethe blue color had disappeared. To this solution, thiourea (75.7 mg,0.994 mmol) was added in one portion at −70° C., and the cooling bathwas removed. The reaction was allowed to warm to room temperature andstirred for 15 hours. The reaction was worked up by filtration to removesolid thiourea S-dioxide, and then partitioned between CH₂Cl₂ and water.The organic layer was removed. The aqueous layer was washed with CH₂Cl₂one more time, and the organic extracts were combined. The organic layerwas washed with aqueous 1N HCl, saturated NaHCO₃ and brine. The organicextracts were dried in vacuo and the residue was purified to by silicagel chromatography to afford 357 mg (75%) of the product as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ −0.01 (s, 9H), 1.05-1.15 (m, 2H), 2.15(s, 3H), 3.69 (s, 3H), 3.78 (d, 2H, J=1 Hz), 4.27-4.39 (m, 2H), 5.11 (s,2H), 9.72 (d, 1H, J=1 Hz) ppm.

4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal

[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde(70 mg, 0.21 mmol) in toluene (2 mL) was heated at 100° C. with2-(triphenyl-phosphanylidene)-propionaldehyde (72.9 mg, 0.23 mmol)overnight. A second portion of2-(triphenyl-phosphanylidene)-propionaldehyde (33 mg, 0.11 mmol) wasadded and the reaction mixture was heated for an additional day. Afterconcentration, the residue was purified by silica gel chromatography toprovide 54 mg (83%) of the desired product as a pale yellow oil. ¹H NMR(300 MHz, CDCl₃) δ 0.00 (s, 9H), 1.10-1.21 (m, 2H), 1.87 (s, 3H), 2.16(s, 3H), 3.67-3.76 (m, 2H), 3.74 (s, 3H), 4.27-4.39 (m, 2H), 5.11 (s,2H), 6.40-6.48 (m, 1H), 9.2 (s, 1H) ppm.

6-(4-Hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

A solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(103 mg, 0.27 mmol) in methanol (5 mL) was cooled to 0° C. A solution ofCeCl₃ (0.68 mL, MeOH: H₂O, 9:1) was added, followed by LiBH₄ (0.14 mL,0.28 mmol of a 2M solution in THF). The ice bath was removed and thereaction mixture was allowed to warm to room temperature. The reactionmixture was stirred for an additional 40 minutes whereupon TLC indicatedcomplete consumption of starting aldehyde. The reaction was worked up byaddition of aqueous 1N HCl (0.5 mL) and the product was extracted withCH₂Cl₂. The organic layer was washed with saturated aqueous sodiumbicarbonate solution and brine. The organic layer was concentrated underreduced pressure and the residue was purified by silica gelchromatography to provide 100 mg (97%) of the product as a clear liquid.¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H), 1.20 (dd, 2H, J=7, 8 Hz), 1.81(s, 3H), 2.13 (s, 3H), 3.38-3.50 (m, 2H), 3.74 (s, 3H), 3.95 (s, 2H),4.27 (dd, 2H, J=7, 8 Hz), 5.08 (s, 2H), 5.17-5.44 (m, 1H) ppm.

6-(2-Hydroxy-ethyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

To a solution of[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde(97 mg, 0.29 mmol) in THF (5 mL) was added an aliquot of a 2 M LiBH₄ inTHF (150 μL, 0.300 mmol). The reaction mixture was stirred at roomtemperature for 1 hour when complete consumption of the startingmaterials was observed by TLC. The reaction mixture was worked up byaddition of an aqueous 1N HCl solution and extraction with EtOAc. Theorganic layer was dried in vacuo and the residue was purified by silicagel chromatography to provide the product. ¹H NMR (300 MHz, CDCl₃) δ0.00 (s, 9H), 1.20 (dd, 2H, J=7, 9 Hz), 2.07 (br s, 1H), 2.14 (s, 3H),2.97 (t, 2H, J=6 Hz), 3.76 (t, 2H, J=6 Hz), 3.77 (s, 3H), 4.32 (dd, 2H,J=7, 8 Hz), 5.08 (s, 2H) ppm.

{2-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-ethoxymethyl}-phosphonicacid diisopropyl ester

A mixture of6-(2-hydroxy-ethyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(79 mg, 0.23 mmol) was heated with bromomethylphosphonic aciddiisopropyl ester (120 mg, 0.46 mmol) in the presence of lithiumt-butoxide (22 mg, 0.27 mmol) in DMF (2 mL) at 70° C. overnight. Thereaction mixture was purified by RP HPLC (acetonitrile and 0.1% aqueousCF₃COOH) to provide the desired product. ¹H NMR (300 MHz, CDCl₃) δ 0.00(s, 9H), 1.13-1.25 (m, 2H), 1.26 (t, 12H, J=6 Hz), 2.12 (s, 3H), 2.98(t, 2H, J=7 Hz), 3.60-3.73 (m, 4H), 3.77 (s, 3H), 4.05-4.16 (m, 2H),4.62-4.74 (m, 2H), 5.07 (s, 2H) ppm; MS (m/z) 539 [M+Na]⁺.

Example 296

Representative compounds of the invention can be prepared as illustratedbelow.

[2-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-ethoxymethyl]-phosphonicacid

To a solution of{2-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-ethoxymethyl}-phosphonicacid diisopropyl ester (7.5 mg, 0.014 mmol) in acetonitrile (2 mL) and2,6-lutidine (25 μL, 0.21 mmol) was added trimethylsilyl bromide (27 μL,0.21 mmol) at room temperature. The reaction was allowed to proceed for18 hours when completion of the reaction was indicated by LCMS. Thereaction was quenched by addition of MeOH and concentration. The residuewas purified by RP-HPLC using a C18 column. The collected product wasdissolved in a solution of 10% TFA/CH₂Cl₂ to assure completedeprotection. The reaction mixture was lyophilized to provide thedesired product. ¹H NMR (300 MHz, CD₃OD) δ 2.12 (s, 3H), 2.98 (t, 2H,J=7 Hz), 3.66-3.76 (m, 4H), 3.78 (s, 3H), 5.21 (s, 2H) ppm; MS (m/z) 331[M−H]⁻.

Example 297

Representative compounds of the invention can be prepared as illustratedbelow.

6-(4-Bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one

Polymer-supported triphenylphosphine (3 mmol/g, 0.5 g) was soaked indichloromethane (10 mL) for 1 hour7-Hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one(100 mg, 0.36 mmol) and carbon tetrabromide (143 mg, 0.43 mmol) wereadded sequentially and the mixture was shaken for 1 hour at roomtemperature. More carbon tetrabromide (143 mg, 0.43 mmol) was added andthe mixture was shaken further for 1 hour The mixture was filtered andthe filtrate was concentrated. The residue was chromatographed on silicagel (0% to 60% ethyl acetate/hexanes) to afford6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-oneas an oil (52 mg, 42%); ¹H NMR (300 MHz, CDCl₃) δ 1.95 (s, 3H), 2.16 (s,3H), 3.44 (d, J=7.2, 2H), 3.78 (s, 3H), 3.98 (s, 2H), 5.21 (s, 2H), 5.68(t, J=7.2 Hz, 1H), 7.71 (brs, 1H) ppm.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phosphonicacid dimethyl ester

A solution of6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one(33 mg, 0.097 mmol) in trimethylphosphite (1.0 mL, 8.5 mmol) was heatedto 100° C. for 1 hour, whereupon complete reaction was indicated byLCMS. The reaction was worked up by removal of the excess reagent underreduced pressure and the residue was purified by silica gelchromatography using EtOAc-hexanes (20-100%) to provide 20 mg (60%) ofthe desired product. ¹H NMR (300 MHz, CDCl₃) δ 1.90 (s, 3H), 2.09 (s,3H), 2.48 (d, 2H, J=22 Hz), 3.38 (t, 2H, J=6 Hz), 3.64 (d, 6H, J=11 Hz),3.72 (s, 3H), 5.14 (s, 2H), 5.33 (q, 1H, J=6 Hz), 7.65 (br s, 1H) ppm;MS (m/z) 371 [M+H]⁺.

Example 298

Representative compounds of the invention can be prepared as illustratedbelow.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phosphonicacid

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phosphonicacid dimethyl ester (18 mg, 0.049 mmol) in acetonitrile (2 mL) was addedTMSBr (63 μL, 0.49 mmol) and 2,6-lutidine (85 μL, 0.73 mmol) at 0° C.The reaction solution was allowed to warm to room temperature andstirred for 2 hours when completion of the reaction was observed byLCMS. The reaction was cooled to 0° C. and quenched by the addition ofMeOH. The reaction mixture was concentrated under reduced pressure andthe residue was purified by RP HPLC using a C18 column with a gradientof H₂O-acetonitrile (5-0%) over 20 minutes to provide 12.2 mg (73%) ofthe product. ¹H NMR (300 MHz, CD₃OD) δ 1.95 (s, 3H), 2.15 (s, 3H), 2.48(d, 2H, J=22 Hz), 3.44 (t, 2H, J=6 Hz), 3.79 (s, 3H), 5.24 (s, 2H), 5.38(q, 1H, J=7 Hz), 6.87 (br s, 1H) ppm; MS (m/z) 341 [M−H]⁻.

Example 299

Representative compounds of the invention can be prepared as illustratedbelow.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monophenyl ester and[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diphenyl ester

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid (49 mg, 0.13 mmol) in DMF (0.4 mL) and phenol (62 mg, 0.65 mmol)was added dicyclohexyl carbodiimide (107 mg, 0.52 mmol) and DMAP (8 mg,0.065 mmol) in DMF (0.6 mL), slowly at 0° C. The reaction was allowed towarm to room temperature and heated to 140° C. for 10 hours. Aftercooling to room temperature the mixture was filtered and extracted withaqueous 1N NaOH solution. The aqueous layer was acidified with aqueous1N HCl and extracted with EtOAc. The organic layer was dried over Na₂SO₄and concentrated to dryness. The residue was purified by RP HPLC toprovide 18.5 mg of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monophenyl ester, as a pale yellow solid and 4.1 mg of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diphenyl ester (minor product) also as a pale yellow solid. Majorproduct: ¹H NMR (300 MHz, CD₃OD) δ 1.82 (s, 3H), 2.16 (s, 3H), 3.46 (d,2H, J=7 Hz), 3.70 (d, 2H, J=8 Hz), 3.77 (s, 3H), 3.96 (s, 2H), 5.25 (s,2H), 5.52 (t, 1H, J=8 Hz), 7.10-7.21 (m, 3H), 7.30 (t, 2H, J=8 Hz) ppm;³¹P (121.4 MHz, CD₃OD) δ 17.3 ppm; MS (m/z) 449.0 [M+H]⁺, 471.2 [M+Na]⁺.Minor product: ¹H NMR (300 MHz, CD₃OD) δ 1.82 (s, 3H), 2.15 (s, 3H),3.47 (d, 2H, J=7 Hz), 3.77 (s, 3H), 3.98-4.06 (m, 4H), 5.25 (s, 2H),5.50-5.61 (m, 1H), 7.10-7.25 (m, 6H), 7.30-7.41 (m, 4H) ppm; ³¹P (121.4MHz, CD₃OD) δ 16.3 ppm; MS (m/z) 525.2 [M+H]⁺, 547.2 [M+Na]⁺.

Example 300

Representative compounds of the invention can be prepared as illustratedbelow.

2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phenoxy-phosphinoyloxy}-propionicacid ethyl ester

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monophenyl ester (18.5 mg, 0.040 mmol) and ethyl (S)-(−)-lactate(47 μL, 0.400 mmol) in pyridine (0.5 mL) was added PyBOP (32 mg, 0.060mmol). The solution was stirred at room temperature for 1 hour, when anadditional portion of PyBOP (21 mg, 0.040 mmol) was added. The solutionwas stirred for another hour and concentrated. The residue was purifiedby HPLC to provide 7.5 mg of the desired product as a clear oil. ¹H NMR(300 MHz, CD₃OD) δ 1.22 and 1.25 (t, 3H, J=7 Hz), 1.42 and 1.50 (d, 3H,J=7 Hz), 1.82 and 1.83 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J=7 Hz), 3.78(s, 3H), 3.89 (d, 1H, J=8 Hz), 3.93-4.02 (m, 3H), 4.10-4.22 (m, 2H),4.94-5.08 (m, 1H), 5.25 (s, 2H), 5.50-5.60 (m, 1H), 7.15-7.27 (m, 3H),7.33-7.41 (m, 2H) ppm; ³¹P (121.4 MHz, CD₃OD) δ 18.9, 20.3 ppm(diastereomers at phosphorus); MS (m/z) 549.2 [M+H]⁺, 571.3 [M+Na]⁺.

Example 301

Representative compounds of the invention can be prepared as illustratedbelow.

2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phenoxy-phosphinoylamino}-propionicacid ethyl ester

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monophenyl ester (20 mg, 0.045 mmol) and L-alanine ethyl esterhydrochloride (68.5 mg, 0.45 mmol) in pyridine (1.0 mL) was added PyBOP(70 mg, 0.14 mmol). After stirring overnight, the mixture wasconcentrated and the residue purified by RP HPLC using a C18 column witha gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 3.6 mg ofthe product as a colorless gel. ¹H NMR (300 MHz, CD₃OD) δ 1.17-1.3 (m,6H), 1.8-1.9 (m, 3H), 2.16 (s, 3H), 3.17 (m, 1H), 3.47 (d, 2H), 3.72-3.8(m, 5H), 3.92-4.2 (m, 4H), 5.25 (s, 2H), 5.54 (m, 1H), 7.18 (m, 3H),7.33 (m, 2H) ppm; ³¹P (121.4 MHz, CD₃OD) δ 24.1, 25.0 ppm (diastereomersat phosphorus); MS (m/z) 546.2 [M−H]⁺.

Example 302

Representative compounds of the invention can be prepared as illustratedbelow.

[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid monomethyl ester

To a solution of[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid diphenyl ester (53 mg, 0.1 mmol) in methanol (0.5 mL) was added anaqueous solution of 1N NaOH (300 μL). After stirring overnight, themixture was concentrated and the residue purified by RP HPLC using a C18column with a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA toprovide 5 mg of the product as a colorless gel, together with thephosphonic acid monophenyl ester (7 mg) and the phosphonic acid dimethylester (14.5 mg). ¹H NMR (300 MHz, CD₃OD) δ 1.84 (s, 3H), 2.16 (s, 3H),3.47 (d, 2H, J=7 Hz), 3.6 (d, 2H, J=12 Hz), 3.75 (d, 3H, J=11 Hz), 3.79(s, 3H), 3.94 (s, 2H), 5.26 (s, 2H), 5.53 (t, 1H, J=7 Hz) ppm; ³¹P(121.4 MHz, CD₃OD) δ 21.5 ppm; MS (m/z) 385.2 [M−H]⁺, 387.1 [M+H]⁺.

Example 303

Representative compounds of the invention can be prepared as illustratedbelow.

(2-{4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester

To a solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(84 mg, 0.22 mmol), (2-amino-ethyl)-phosphonic acid diethyl esteroxalate (91 mg, 0.33 mmol), and sodium triacetoxyborohydride (93 mg,0.44 mmol) in DMF (1.5 mL) was added acetic acid (60 μL, 1.0 mmol) atroom temperature. The solution was stirred for 2 days when it wasquenched by addition of saturated aqueous sodium bicarbonate solutionand EtOAc. The organic layer was separated and concentrated underreduced pressure. The residue was purified by RP HPLC using a C18 columnwith a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 115mg (96%) of the product as an oil. ¹H NMR (300 MHz, CDCl₃) δ 0.04 (s,9H), 1.16-1.27 (m, 2H), 1.34 (t, 6H, J=7 Hz), 1.94 (s, 3H), 2.18 (s,3H), 2.20-2.31 (m, 2H), 3.13-3.31 (m, 2H), 3.48 (d, 2H, J=7 Hz), 3.54(s, 2H), 3.78 (s, 3H), 4.14 (pent, 4H, J=7 Hz), 4.30-4.37 (m, 2H), 5.13(s, 2H), 5.65 (t, 1H, J=7 Hz), 6.23 (br s, 2H) ppm; ³¹P (121.4 MHz,CDCl₃) δ 27.8 ppm; MS (m/z) 542.3 [M+H]⁺, 564.2 [M+Na]⁺.

{2-[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl}-phosphonicacid

A solution of(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (30 mg, 0.055 mmol), TMSBr (72 μL, 0.55 mmol), and2,6-lutidine (64 μL, 0.55 mmol) was stirred in CH₂Cl₂ (1 mL) and DMF(0.5 mL) for 1 hour at ambient temperature. The reaction mixture waspurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 7.8 mg of the product as a whitesolid. ¹H NMR (300 MHz, CD₃OD) δ 1.96 (s, 3H), 1.95-2.07 (m, 2H), 2.16(s, 3H), 3.10-3.24 (m, 2H), 3.51 (d, 2H, J=7 Hz), 3.57 (s, 2H), 3.81 (s,3H), 5.25 (s, 2H), 5.73 (t, 1H, J=7 Hz) ppm; ³¹P (121.4 MHz, CD₃OD) δ20.2 ppm; ¹⁹F NMR (282.6 MHz, CD₃OD) δ −74.0 ppm; MS (m/z) 386.3 [M+H]⁺.

Example 304

Representative compounds of the invention can be prepared as illustratedbelow.

[2-(Methanesulfonyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester

A solution of(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (45 mg, 0.092 mmol) in CH₂Cl₂ (0.5 mL) was stirredwith methanesulfonyl chloride (21 μL, 0.28 mmol) and pyridine (45 μL,0.55 mmol) at ambient temperature overnight. The reaction was quenchedby addition of 2 drops of water. The reaction mixture was concentratedand purified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 36 mg of the product (63%) as aclear gel. ¹H NMR (300 MHz, CDCl₃) δ 0.05 (s, 9H), 1.18-1.29 (m, 2H),1.29 (t, 6H, J=7 Hz), 1.85 (s, 3H), 2.00-2.13 (m, 2H), 2.19 (s, 3H),2.85 (s, 3H), 3.32-3.43 (m, 2H), 3.47 (d, 2H, J=7 Hz), 3.69 (s, 2H),3.79 (s, 3H), 4.05 (pent, 4H, J=7 Hz), 4.30-4.37 (m, 2H), 5.13 (s, 2H),5.45 (t, 1H, J=7 Hz) ppm; ³¹P (121.4 MHz, CD₃Cl) δ 27.5 ppm; MS (m/z)642.2 [M+Na]⁺.

(2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-methanesulfonyl-amino}-ethyl)-phosphonicacid

A solution of[2-(methanesulfonyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester (18 mg, 0.029 mmol) in acetonitrile (0.5 mL) wasstirred with TMSBr (38 μL, 0.29 mmol) and 2,6-lutidine (34 μL, 0.29mmol) for 2 hours at room temperature. The reaction was worked up byaddition of EtOAc and aqueous 1N HCl. The organic layer was washed withbrine and the solvent was removed in vacuo. The residue was suspended ina solution of 10% TFA-CH₂Cl₂ for 10 minutes before it was dried toprovide 9.9 mg of the desired product (73%) as a white solid. ¹H NMR(300 MHz, DMSO-d6) δ 1.76 (s, 3H), 1.76-1.88 (m, 2H), 2.10 (s, 3H), 2.87(s, 3H), 3.24-3.35 (m, 2H), 3.39 (d, 2H, J=7 Hz), 3.65 (s, 2H), 3.75 (s,3H), 5.22 (s, 2H), 5.41-5.48 (m, 1H) ppm; ³¹P (121.4 MHz, DMSO-d6) δ21.4 ppm; MS (m/z) 464.1 [M+H]⁺.

Example 305

Representative compounds of the invention can be prepared as illustratedbelow.

[2-(Acetyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester

To a solution of(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (32 mg, 0.059 mmol) in acetic acid (0.5 mL) was addedacetic anhydride (0.5 mL). The solution was stirred at room temperaturefor 90 minutes when it was quenched by addition of 2 drops of water. Thesolution was dried in vacuo and the residue was purified by RP HPLCusing a C18 column with a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1%TFA to provide 28 mg of the product (81%) as a clear gel. The NMR dataof this compound shows two rotamers in a ratio of 70:30. ¹H NMR (300MHz, CDCl₃) δ 0.05 (s, 9H), 1.17-1.27 (m, 2H), 1.30 and 1.31 (t, 6H, J=7Hz), 1.70-1.79 (m, 2H), 1.76 (s, 3H), 2.00 (s, 3H), 2.18 (s, 3H),3.40-3.52 (m, 2H), 3.46 (d, 2H, J=7 Hz), 3.77 (s, 3H), 3.79 and 3.93 (s,3H), 4.07 (pent, 4H, J=7 Hz), 4.27-4.35 (m, 2H), 5.13 (s, 2H), 5.22-5.30(m, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 27.5 and 28.9 ppm; MS (m/z) 584.1[M+H]⁺, 606.2 [M+Na]⁺.

(2-{Acetyl-[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-amino}-ethyl)-phosphonicacid

To a solution of[2-(acetyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester (14 mg, 0.024 mmol) in acetonitrile (0.5 mL) wasadded TMSBr (31 μL, 0.24 mmol) and 2,6-lutidine (28 μL, 0.24 mmol). Thesolution was stirred at room temperature for 1 hour. The reaction wasquenched by addition of methanol and aqueous 1N HCl. The product wasextracted with EtOAc. The combined organic extracts were dried overNa₂SO₄ and concentrated in vacuo. The product was purified by RP HPLCusing a C18 column with a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1%TFA to provide 5.4 mg of the product (53%) as a white solid. The NMRdata of this compound shows two rotamers. ¹H NMR (300 MHz, CDCl₃) δ 1.67and 1.73 (s, 3H), 1.85-2.12 (m, 5H), 2.13 (s, 3H), 3.30-3.61 (m, 4H),3.75 (s, 3H), 3.76 (br s, 2H), 5.17 (s, 2H), 5.31 (br s, 1H) ppm; ³¹P(121.4 MHz, CDCl₃) δ 27.5 and 28.8 ppm; MS (m/z) 428.2 [M+H]⁺, 450.2[M+Na]⁺.

Example 306

Representative compounds of the invention can be prepared as illustratedbelow.

[2-(Benzyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester

A solution of(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (30 mg, 0.055 mmol), benzaldehyde (5.6 μL, 0.055mmol), and sodium triacetoxyborohydride (23 mg, 0.11 mmol) was stirredwith acetic acid (15.7 μL, 0.28 mmol) in DMF (0.5 mL) at roomtemperature over night. The reaction was quenched with a 10% aqueousNa₂CO₃ solution and the product was extracted with EtOAc. The organiclayer was dried and concentrated under reduced pressure. The product waspurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 15 mg of the product (43%) as aclear gel. ¹H NMR (300 MHz, CDCl₃) δ 0.02 (s, 9H), 1.18-1.25 (m, 2H),1.24 (t, 6H, J=7 Hz), 1.86 (s, 3H), 1.88-2.02 (m, 2H), 2.16 (s, 3H),2.65-2.74 (m, 2H), 3.93 (s, 2H), 3.46 (br d, 4H, J=7 Hz), 3.76 (s, 3H),4.00 (pent, 4H, J=7 Hz), 4.25-4.34 (m, 2H), 5.11 (s, 2H), 5.34-5.43 (m,1H), 7.18-7.33 (m, 5H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 30.9 ppm; MS (m/z)632.4 [M+H]⁺, 654.3 [M+Na]⁺.

(2-{Benzyl-[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-amino}-ethyl)-phosphonicacid

A solution of(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (15 mg, 0.024 mmol) in acetonitrile (0.5 mL) wastreated with TMSBr (31 μL, 0.24 mmol) and 2,6-lutidine (28 μL, 0.24mmol). The solution was stirred at ambient temperature for 1 hour, whenit was quenched with methanol. The solvent was removed under reducedpressure and the residue was purified by RP HPLC using a C18 column witha gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 11 mg ofthe product (93%) as a white solid. ¹H NMR (300 MHz, CD₃OD) δ 1.89 (s,3H), 2.03-2.15 (m, 2H), 2.14 (s, 3H), 3.30-3.47 (m, 2H), 3.50 (br s,2H), 3.62 (br s, 2H), 3.79 (s, 3H), 4.28 (s, 2H), 5.23 (s, 2H), 5.76 (brs, 1H), 7.46 (br s, 5H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 20.1 ppm; MS (m/z)476.3 [M+H]⁺, 498.3 [M+Na]⁺.

Example 307

Representative compounds of the invention can be prepared as illustratedbelow.

[2-(Formyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester

To a solution of(2-{4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (74 mg, 0.14 mmol) in formic acid (1 mL) was addedformic anhydride (1 mL) and the solution was stirred at room temperaturefor 1 hour. The reaction mixture was concentrated and the crude productcarried onto the next step. The NMR data of this compound shows tworotamers with the ratio of 70:30. ¹H NMR (300 MHz, CDCl₃) δ 0.05 (s,9H), 1.18-1.28 (m, 2H), 1.28 and 1.30 (t, 6H, J=7 Hz), 1.74 (s, 3H),1.84-2.08 (m, 2H), 2.19 (s, 3H), 3.34-3.45 (m, 2H), 3.47 (d, 2H, J=7Hz), 3.72 and 3.87 (s, 2H), 3.78 and 3.79 (s, 3H), 4.06 and 4.07 (pent,4H, J=7 Hz), 4.26-4.37 (m, 2H), 5.13 (s, 2H), 5.30-5.46 (m, 1H), 8.03and 8.19 (s, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 27.5 and 28.1 ppm; MS(m/z) 570.1 [M+H]⁺, 592.2 [M+Na]⁺.

(2-{Formyl-[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-amino}-ethyl)-phosphonicacid

To a solution of crude[2-(formyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonicacid diethyl ester (78 mg, 0.14 mmol) in acetonitrile (1 mL) was addedTMSBr (177 μL, 1.4 mmol) and 2,6-lutidine (163 μL, 1.4 mmol). Thesolution was stirred at room temperature for 1 hour when it was quenchedby addition of methanol and 1N aqueous HCl. The product was extractedwith EtOAc and purified by RP HPLC using a C18 column with a gradient ofH₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 29 mg of the product asa white solid. The NMR data of this compound shows two rotamers with theratio of approximately 70:30. ¹H NMR (300 MHz, CD₃OD) δ 1.62 and 1.64(s, 3H), 1.83-1.98 (m, 2H), 2.16 (s, 3H), 3.38-3.55 (m, 4H), 3.78 (s,3H), 3.80 and 3.91 (s, 2H), 5.22 (s, 2H), 5.39-5.52 (m, 1H), 8.03 and8.18 (s, 1H) ppm; MS (m/z) 414.2 [M+H]⁺, 436.2 [M+Na]⁺.

Example 308

Representative compounds of the invention can be prepared as illustratedbelow.

({4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-methyl)-phosphonicacid diethyl ester

To a solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(500 mg, 1.33 mmol), (2-aminomethyl)phosphonic acid diethyl esteroxalate (376 mg, 1.46 mmol), sodium triacetoxyborohydride (563 mg, 2.66mmol) in DMF (10 mL) was added acetic acid (380 μL, 6.65 mmol) at roomtemperature. The solution was stirred overnight when it was quenched byaddition of saturated aqueous sodium bicarbonate solution and EtOAc. Theorganic layer was separated and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to provide 500 mg(71%) of the product as an oil. ¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H),1.13-1.23 (m, 2H), 1.25 and 1.27 (t, 6H, J=7 Hz), 1.65-1.75 (m, 2H),1.77 (s, 3H), 2.13 (s, 3H), 2.80 (s, 1H), 3.14 (s, 2H), 3.41 (d, 2H, J=7Hz), 3.73 (s, 3H), 4.08 and 4.09 (pent, 4H, J=7 Hz), 4.20-4.30 (m, 2H),5.08 (s, 2H), 5.30 (t, 1H, J=7 Hz) ppm; ³¹P (121.4 MHz, CDCl₃) δ 26.5ppm; MS (m/z) 528.1 [M+H]⁺, 550.2 [M+Na]⁺.

{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-methyl}-phosphonicacid

To a solution of({4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-methyl)-phosphonicacid diethyl ester (20 mg, 0.038 mmol) in DMF (0.5 mL) was added TMSBr(49 μL, 0.38 mmol) and 2,6-lutidine (44 μL, 0.38 mmol). The solution wasstirred at room temperature for 1 hour when it was quenched by additionof methanol. The product was purified by RP HPLC using a C18 column witha gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 5.6 mg ofthe product as a white solid. ¹H NMR (300 MHz, CD₃OD and CDCl₃) δ 1.93(s, 3H), 2.13 (s, 3H), 2.94 (br d, 2H, J=11 Hz), 3.42-3.53 (m, 2H), 3.60(s, 2H), 3.78 (s, 3H), 5.22 (s, 2H), 5.71 (br s, 1H) ppm; ³¹P (121.4MHz, CDCl₃) δ 8.5 ppm; MS (m/z) 372.2 [M+H]⁺, 743.2 [2M+H]⁺.

Example 309

Representative compounds of the invention can be prepared as illustratedbelow.

2-({2-[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl}-phenoxy-phosphinoyloxy)-propionicacid ethyl ester

A solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(188 mg, 0.5 mmol) was stirred with2-[(2-aminoethyl)phenoxy-phosphinoyloxy]-propionic acid ethyl esteracetic acid salt (315.8 mg, 0.75 mmol) in CH₂Cl₂ (3 mL) for 2 hours atambient temperature. Sodium triacetoxyborohydride (159 mg, 0.75 mmol)was added to the solution and the reaction was allowed to proceed for 1hour. The reaction was quenched by addition of a saturated aqueoussolution of NaHCO₃ and the product was extracted with EtOAc. The organiclayer was removed under reduced pressure and the residue was resuspendedin a 10% TFA/CH₂Cl₂ for 1 hour. The reaction mixture was concentratedand the product was purified by RP HPLC using a C18 column with agradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 198 mg ofthe product as a white solid. The NMR data of this compound shows twodiastereomers at phosphorus in a ratio of approximately 45:55. ¹H NMR(300 MHz, CD₃OD) δ 1.23 and 1.24 (t, 3H, J=7 Hz), 1.38 and 1.52 (d, 3H,J=7 Hz), 1.97 and 1.98 (s, 3H), 2.14 (s, 3H), 2.44-2.66 (m, 2H),3.31-3.48 (m, 2H), 3.51 (d, 2H, J=7 Hz), 3.66 (d, 2H, J=5 Hz), 3.80 (s,3H), 4.10-4.27 (m, 2H), 4.90-5.10 (m, 1H), 5.20 (s, 2H), 5.73-5.82 (m,1H), 7:15-7.27 (m, 3H), 7.35-7.45 (m, 2H) ppm; ³¹P (121.4 MHz, CD₃OD) δ22.6, 24.3 ppm; MS (m/z) 561.9 [M+H]⁺.

Example 310

Representative compounds of the invention can be prepared as illustratedbelow.

2-[Hydroxy-(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphinoyloxy]-propionicacid ethyl ester

A solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(38 mg, 0.1 mmol) was stirred with2-[(2-aminoethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl esteracetic acid (63 mg, 0.15 mmol) in CH₂Cl₂ (1 mL) for 2 hours at ambienttemperature. Sodium triacetoxyborohydride (32 mg, 0.15 mmol) was addedto the solution and the reaction was allowed to proceed for 1 hour. Thereaction was quenched by addition of a saturated aqueous solution ofNaHCO₃ and the product was extracted with EtOAc. The organic layer wasremoved under reduced pressure and the residue was re-suspended in 10%TFA/CH₂Cl₂ for 1 hour. The reaction mixture was concentrated and theproduct was purified by RP HPLC using a C18 column with a gradient ofH₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 15 mg of the product(154-2). ¹H NMR (300 MHz, CDCl₃) δ 0.04 (s, 9H), 1.15-1.24 (m, 2H), 1.26(t, 3H, J=7 Hz), 1.48 (d, 3H, J=7 Hz), 1.93 (s, 3H), 2.10-2.25 (m, 2H),2.18 (s, 3H), 3.10-3.31 (m, 2H), 3.48 (d, 2H, J=7 Hz), 3.48-3.61 (m,2H), 3.77 (s, 3H), 4.04-4.21 (m, 2H), 4.29-4.40 (m, 2H), 4.81-4.92 (m,1H), 5.13 (s, 2H), 5.64 (t, 1H, J=7 Hz), 8.70-9.11 (m, 3H) ppm; 31P(121.4 MHz, CDCl₃) δ 21.9 ppm; MS (m/z) 586.3 [M+H]⁺, 1171.4 [2M+H]⁺.

2-(Hydroxy-{2-[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl}-phosphinoyloxy)-propionicacid

A solution of2-[hydroxy-(2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphinoyloxy]-propionicacid ethyl ester (15 mg, 0.026 mmol) in 10% TFA-CH₂Cl₂ (1 mL) wasstirred at ambient temperature for 10 minutes. The reaction was workedup by removal of the solvent. The residue was dissolved in THF (0.5 mL)and water (0.4 mL) and 1N aqueous NaOH solution (0.1 mL) was added. Thesolution was stirred at room temperature for 20 minutes when it wasacidified with 1N aqueous HCl solution. The resulting solution waspurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 6.8 mg of the product as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 1.38 (d, 3H, J=7 Hz), 1.91 (s, 3H),2.13 (s, 3H), 2.12-2.28 (m, 2H), 3.12-3.33 (m, 2H), 3.41 (d, 2H, J=6Hz), 3.56 (br s, 2H), 3.75 (s, 3H), 4.71-4.88 (m, 1H), 5.16 (s, 2H),5.58-5.71 (m, 1H), 7.88 (br s, 3H), 8.60 (br s, 1H), 8.78 (br s, 1H)ppm; ³¹P (121.4 MHz, CDCl₃) δ 22.0 ppm; MS (m/z) 458.3 [M+H]⁺, 480.3[M+Na]⁺.

Example 311

Representative compounds of the invention can be prepared as illustratedbelow.

{1-Cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonicacid diethyl ester

To a solution of diethyl cyanomethylphosphonate (241 mg, 1.38 mmol) inTHF (1 mL) was added a THF solution of sodium bis(trimethysilyl)amide(1.0 M, 1.13 mL, 1.15 mmol). After stirring for 30 minutes, the solutionwas added dropwise to a solution of6-(4-bromo-3-methyl-but-2-enyl)-7-hydroxy-5-methoxy-4-methyl-3H-isobenzofuran-1-one(100 mg, 0.23 mmol) in THF (1 mL). The resulting mixture was allowed tostir at room temperature for one hour before saturated aqueous ammoniumchloride was added. The reaction mixture was extracted with ethylacetate. The organic layer was dried over sodium sulfate andconcentrated to dryness. The residue was purified by silica gel columnchromatography, affording 110 mg (90%) of the desired product. ¹H NMR(300 MHz, CDCl₃) δ 0.04 (s, 9H), 1.24 (dd, J=7, 8 Hz, 2H), 1.36 (t, 6H),1.86 (s, 3H), 2.17 (s, 3H), 2.43-2.57 (m, 2H), 3.04-3.17 (m, 1H), 3.47(d, J=7.2 Hz, 2H), 3.79 (s, 3H), 4.12-4.37 (m, 6H), 5.13 (s, 2H), 5.44(t, J=7.2 Hz, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 18.18 ppm; MS (m/z) 560[M+Na]⁺.

[1-Cyano-5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid diethyl ester

{1-Cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonicacid diethyl ester (25 mg, 0.047 mmol) was dissolved in a solution of10% TFA/CH₂Cl₂ (5 mL) and stirred at room temperature for 2 hours. Thereaction mixture was dried under reduced pressure and the product waspurified by RP-HPLC to provide 16 mg (80%) of the desired product as awhite solid. ¹H NMR (300 MHz, CDCl₃) δ 1.38 (t, 6H), 1.86 (s, 3H), 2.15(s, 3H), 2.40-2.58 (m, 2H), 3.01-3.14 (m, 1H), 3.45 (d, J=7.2 Hz, 2H),3.79 (s, 3H), 4.18-4.30 (m, 4H), 5.21 (s, 2H), 5.48 (t, J=7.2 Hz, 1H)ppm; 31P (121.4 MHz, CDCl₃) δ 18.09 ppm; MS (m/z) 436 [M−H]−, 438[M+H]+.

Example 312

Representative compounds of the invention can be prepared as illustratedbelow.

[1-Cyano-5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonicacid

To a solution of{1-cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonicacid diethyl ester (35 mg, 0.065 mmol) in acetonitrile (2 mL) was addedTMSBr (180 μL, 1.38 mmol) and 2,6-lutidine (160 μL, 1.38 mmol). Thereaction solution was allowed stir at room temperature for one hourbefore quenching with MeOH. The reaction mixture was dried under reducedpressure and the residue was purified by RP HPLC using a C18 column witha gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 15 mg(60%) of the desired product. ¹H NMR (300 MHz, CD₃OD) δ 1.86 (s, 3H),2.15 (s, 3H), 2.38-2.57 (m, 2H), 3.17-3.28 (m, 1H), 3.44 (d, J=7.2 Hz,2H), 3.80 (s, 3H), 5.25 (s, 2H), 5.47 (t, J=7.2 Hz, 1H) ppm; ³¹P (121.4MHz, CD₃OD) δ 15.28 ppm; MS (m/z) 380 [M−H]⁻, 382 [M+H]⁺.

Example 313

Representative compounds of the invention can be prepared as illustratedbelow.

{1-Cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-1,3-dimethyl-pent-3-enyl}-phosphonicacid diethyl ester

To a solution of{1-cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonicacid diethyl ester (45 mg, 0.084 mmol) in THF (0.5 mL) was added sodiumbis(trimethysilyl)amide (1.0 M, 1.13 mL, 1.15 mmol). After stirring for20 minutes, iodomethane (52 μL, 0.84 mmol) was added dropwise and theresulting mixture was allowed to stir at room temperature for 2 hours.The reaction mixture was quenched with saturated aqueous ammoniumchloride and extracted with ethyl acetate. The organic layer was driedover sodium sulfate and concentrated to dryness. The residue waspurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to afford 6.6 mg (23%) of the desiredproduct. ¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H), 1.16 (dd, J=7, 8 Hz,2H), 1.31 (t, 6H), 1.38 (d, 3H), 1.92 (s, 3H), 2.17 (s, 3H), 2.23 (m,1H), 2.65 (m, 1H), 3.30-3.42 (m, 2H), 3.73 (s, 3H), 4.14-4.27 (m, 6H),5.08 (s, 2H), 5.28 (t, J=7.2 Hz, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 22.26ppm; MS (m/z) 574 [M+Na]⁺.

[1-Cyano-5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-1,3-dimethyl-pent-3-enyl]-phosphonicacid

To a solution of{1-cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-1,3-dimethyl-pent-3-enyl}-phosphonicacid diethyl ester (18 mg, 0.04 mmol) in DMF (0.5 mL) and DCM (0.5 mL)was added TMSBr (51 μL, 0.4 mmol) and 2,6-lutidine (46 μL, 0.4 mmol).The reaction solution was allowed stir at room temperature overnightbefore quenching with MeOH. The reaction mixture was dried under reducedpressure and the residue was purified by RP HPLC using a C18 column witha gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 4.5 mg(33%) of the desired product. ¹H NMR (300 MHz, CD₃OD) δ 1.37 (d, 3H),1.87 (s, 3H), 2.13 (s, 3H), 2.26 (m, 1H), 2.64 (m, 1H), 3.39 (m, 2H),3.75 (s, 3H), 5.18 (s, 2H), 5.34 (m, 1H) ppm; ³¹P (121.4 MHz, CD₃OD) δ21.47 ppm; MS (m/z) 422 [M−H]⁻, 424 [M+H]⁺.

Example 314

Representative compounds of the invention can be prepared as illustratedbelow.

2-Ethyl-4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal

A solution of[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde(1.5 g, 4.46 mmol) in toluene (14 mL) was heated at 100° C. with2-(triphenyl-phosphanylidene)-butyraldehyde (1.68 g, 5.35 mmol)overnight. A second portion of2-(triphenyl-phosphanylidene)-butyraldehyde (495 mg, 1.49 mmol) wasadded and the reaction mixture was heated for an additional day. Afterconcentration, the residue was purified by silica gel chromatography toprovide 1.3 g (83%) of the desired product as oil. ¹H NMR (300 MHz,CDCl₃) δ 0.01 (s, 9H), 1.03 (t, 3H), 1.10-1.21 (m, 2H), 2.15 (s, 3H),2.15-2.44 (m, 2H), 3.67-3.76 (m, 2H), 3.74 (s, 3H), 4.31-4.36 (m, 2H),5.10 (s, 2H), 6.34-6.38 (m, 1H), 9.28 (s, 1H) ppm.

6-(3-Hydroxymethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

A solution of2-ethyl-4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal(1.3 g, 3.30 mmol) in methanol (10 mL) and THF (10 mL) was cooled to 0°C. A solution of CeCl₃ (8.25 mL, 0.4M, MeOH: H₂O, 9:1) was added,followed by LiBH₄ (1.66 mL, 3.30 mmol of a 2M solution in THF). The icebath was removed and the reaction mixture was allowed to warm to roomtemperature. The reaction mixture was stirred for an additional 40minutes, whereupon TLC indicated complete consumption of startingaldehyde. The reaction was worked up by addition of aqueous 1N HCl andthe product was extracted with EtOAc. The organic layer was washed withsaturated aqueous sodium bicarbonate solution and brine. The organiclayer was concentrated under reduced pressure and the residue waspurified by silica gel chromatography to provide 948 mg (73%) of theproduct as colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H), 1.07(t, 3H), 1.20 (dd, 2H, J=7, 8 Hz), 2.13 (s, 3H), 2.38-2.50 (m, 2H), 3.77(s, 3H), 3.99 (s, 2H), 4.27 (dd, 2H, J=0.7, 8 Hz), 5.08 (s, 2H), 5.34(t, J=7.2 Hz, 1H) ppm.

6-(3-Bromomethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

Polymer-supported triphenylphosphine (3 mmol/g, 0.66 g) was soaked indichloromethane (6 mL) for 1 hour6-(3-Hydroxymethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(260 mg, 0.66 mmol) and carbon tetrabromide (657 mg, 1.98 mmol) wereadded sequentially and the mixture was shaken for 1 hour at roomtemperature. The mixture was filtered and the filtrate was concentrated.The residue was purified by silica gel chromatography to provide 233 mg(77%) of the product as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 0.00(s, 9H), 1.08 (t, 3H), 1.20 (dd, 2H, J=7, 8 Hz), 2.14 (s, 3H), 2.35-2.43(m, 2H), 3.44 (d, J=7.2, 2H), 3.73 (s, 3H), 3.95 (s, 2H), 4.27 (dd, 2H,J=7, 8 Hz), 5.08 (s, 2H), 5.53 (t, J=7.2 Hz, 1H) ppm.

[2-Ethyl-4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-but-2-enyl]-phosphonicacid

A solution of6-(3-bromomethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(230 mg, 0.5 mmol) in trimethylphosphite (1.5 mL, 12.75 mmol) was heatedto 100° C. for 4 hours. The reaction was worked up by removal of excesstrimethylphosphite under reduced pressure. The residue was dissolved inacetonitrile (1 mL) and TMSBr (646 μL, 5.0 mmol) and 2,6-lutidine (580μL, 5.0 mmol) were added at 0° C. The reaction solution was allowed towarm to room temperature and stirred for 4 hours. The reaction wascooled to 0° C. and quenched with addition of MeOH. The reaction mixturewas dried under reduced pressure and the residue was purified by RP HPLCusing a C18 column with a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1%TFA to provide 77 mg (58%) of the product. ¹H NMR (300 MHz, CD₃OD) δ1.08 (t, 3H), 2.16 (s, 3H), 2.43 (m, 2H), 2.48 (d, 2H, J=22 Hz), 3.46(t, 2H, J=6 Hz), 3.79 (s, 3H), 5.25 (s, 2H), 5.38 (q, 1H, J=7 Hz) ppm.;³¹P (121.4 MHz, CD₃OD) δ 25.65 ppm.; MS (m/z) 355 [M−H]⁻, 357 [M+H]⁺.

Example 315

Representative compounds of the invention can be prepared as illustratedbelow.

{1-Cyano-3-ethyl-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-pent-3-enyl}-phosphonicacid diethyl ester

To a solution of diethyl cyanomethylphosphonate (233 mg, 1.32 mmol) inTHF (1 mL) was added a THF solution of sodium bis(trimethysilyl)amide(1.0 M, 1.21 mL, 1.21 mmol). After stirring for 30 minutes, the solutionwas added dropwise to a solution of6-(3-bromomethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(100 mg, 0.22 mmol) in THF (1 mL). The resulting mixture was allowed tostir at room temperature overnight before saturated aqueous ammoniumchloride was added. The reaction mixture was extracted with ethylacetate. The organic layer was dried over sodium sulfate andconcentrated to dryness. The residue was purified by preparativereverse-phase HPLC, affording 51 mg (42%) of the desired product. ¹H NMR(300 MHz, CDCl₃) δ 0.04 (s, 9H), 1.07 (t, 3H), 1.24 (dd, 2H, J=7, 8 Hz),1.36 (t, 6H), 2.12 (m, 1H), 2.18 (s, 3H), 2.35-2.47 (m, 2H), 2.67 (m,1H), 3.00-3.14 (m, 1H), 3.44 (d, J=7.2, 2H), 3.79 (s, 3H), 4.12-4.37 (m,6H), 5.13 (s, 2H), 5.38 (t, J=7.2 Hz, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ18.26 ppm; MS (m/z) 574 [M+Na]⁺.

[1-Cyano-3-ethyl-5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-pent-3-enyl]-phosphonicacid

{1-Cyano-3-ethyl-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-pent-3-enyl}-phosphonicacid diethyl ester (19.5 mg, 0.035 mmol) was dissolved in a solution of10% TFA/CH₂Cl₂ (2 mL) and stirred at room temperature for 10 minutes.The reaction mixture was dried under reduced pressure and purified byRP-HPLC to provide 9.5 mg (61%) of the desired product. This materialwas dissolved in DMF (0.5 mL) and DCM (0.5 mL) and TMSBr (27 μL, 0.2mmol) and 2,6-lutidine (23 μL, 0.2 mmol) were added. The reactionsolution was allowed stir at room temperature overnight before quenchingwith MeOH. The reaction mixture was dried under reduced pressure and theresidue was purified by RP HPLC using a C18 column with a gradient ofH₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 5.1 mg (65%) of thedesired product as a white solid. ¹H NMR (300 MHz, CD₃OD) δ 1.10 (t,3H), 2.16 (s, 3H), 2.23-2.52 (m, 3H), 2.67 (m, 1H), 3.05-3.20 (m, 1H),3.48 (d, J=7.2, 2H), 3.81 (s, 3H), 5.26 (s, 2H), 5.43 (t, J=7.2 Hz, 1H)ppm; ³¹P (121.4 MHz, CD₃OD) δ 14.18 ppm; MS (m/z) 394 [M−H]⁻, 396[M+H]⁺.

Example 316

Representative compounds of the invention can be prepared as illustratedbelow.

{2-Ethyl-4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enyloxymethyl}-phosphonicacid diisopropyl ester

To a solution of bromomethylphosphonate diisopropyl ester (680 mg, 2.62mmol) and6-(3-hydroxymethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(688 mg, 1.75 mmol) in DMF (3 mL) was added lithium t-butoxide (1.0M inTHF; 2.6 mL). The reaction was heated at 70° C. for 2 hours. Aftercooling to ambient temperature, more bromomethylphosphonate diisopropylester (680 mg, 2.62 mmol) and lithium t-butoxide (1.0M in THF; 2.6 mL)were added. The reaction mixture was heated at 70° C. for a furtherhour, cooled, poured into a solution of lithium chloride (5% aqueous)and extracted with ethyl acetate. The organic extract was dried and theproduct was purified by chromatography on silica gel, eluting withhexane-ethyl acetate to provide 347 mg (35%) of the product as acolorless oil. ¹H NMR (300 MHz, CDCl₃) δ 0.04 (s, 9H), 1.09 (t, 3H,J=7.5 Hz), 1.20-1.26 (m, 2H), 1.31 (t, 12H, J=6 Hz), 2.18 (s, 3H), 2.29(q, 2H, J=7.5 Hz), 3.5 (m, 2H), 3.59 (d, 2H, J=8.7 Hz), 3.78 (s, 3H),3.98 (s, 2H), 4.28-4.35 (m, 2H), 4.6-4.8 (m, 2H), 5.13 (s, 2H), 5.4 (t,1H, J=7 Hz) ppm; ³¹P (121.4 MHz, CDCl₃) δ 20.26 ppm; MS (m/z) 593.3[M+Na]⁺.

[2-Ethyl-4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-but-2-enyloxymethyl]-phosphonicacid

To a solution of{2-ethyl-4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enyloxymethyl}-phosphonicacid diisopropyl ester (347 mg, 0.61 mmol) in acetonitrile (5 mL) wasadded 2,6-lutidine (0.71 mL, 6.1 mmol) and bromotrimethylsilane (0.786mL, 6.1 mmol). The mixture was stirred at room temperature for 3 hours,quenched with methanol (5 mL), concentrated, and partitioned betweenethyl acetate and 1N HCl (aqueous). The organic layer was concentratedto give the free phosphonic acid as a colorless oil (205 mg, 70%). Thismaterial (20 mg) was dissolved in a solution of trifluoroacetic acid(0.3 mL) and dichloromethane (2.7 mL) and stirred for 30 minutes atambient temperature. After concentration, the residue was purified by RPHPLC using a C18 column with a gradient of H₂O, 0.1% TFA-acetonitrile,0.1% TFA to provide the product, after lyophilization, as a white solid(10 mg). ¹H NMR (300 MHz, CDCl₃) δ 1.007 (t, 3H, J=7.5 Hz), 2.13 (s,3H), 2.32 (q, 2H, J=7.5 Hz), 3.41 (d, 2H, J=6.3 Hz), 3.56 (d, 2H, J=9Hz), 3.75 (s, 3H), 3.95 (s, 2H), 5.16 (s, 2H), 5.43 (t, 1H, J=6.3 Hz)ppm; ³¹P (121.4 MHz, CDCl₃) δ 22.8 ppm; MS (m/z) 385.2 [M−H]⁺, 387.1[M+H]⁺.

Example 317

Representative compounds of the invention can be prepared as illustratedbelow.

6-Allyloxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethylester

To a solution of 6-allyloxy-4-hydroxy-3-methyl-phthalic acid dimethylester (8.06 g, 28.8 mmol) [synthesized according to: J. W. Patterson,Tetrahedron, 1993, 49, 4789-4798] and pyridine (11.4 g, 144.0 mmol) indichloromethane (DCM) (20 mL) at 0° C. was added triflic anhydride(12.19 g, 43.2 mmol). The reaction was stirred at 0° C. for 2 hoursafter which additional triflic anhydride (3 mL) was added. Stirring at0° C. was continued for an additional hour. The reaction mixture waspoured into a mixture of DCM and HCl (1N). The layers were separated andthe aqueous layer was extracted with DCM. The combined organic layerswere dried over sodium sulfate. Filtration and evaporation of solventsin vacuo yielded a crude product, which was purified by silica gelchromatography to provide 8.39 g of the product as an oil. ¹H NMR (300MHz, CDCl₃): δ=2.32 (s, 3H), 3.89 (s, 6H), 4.60 (m, 2H), 5.33 (d, J=9.3Hz, 1H), 5.41 (d, J=18.6 Hz, 1H), 5.95 (m, 1H), 6.95 (s, 1H) ppm; ¹⁹FNMR (282 MHz, CDCl₃): δ=−74 ppm.

6-Hydroxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethylester

To a solution of6-allyloxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethylester (8.39 g, 20.3 mmol) in toluene (20 mL) was addedtetrakistriphenylphosphine palladium (0.47 g, 0.40 mmol) anddiethylamine (2.97 g, 40.86 mmol) at room temperature under anatmosphere of nitrogen. Stirring at room temperature was continued untilall starting material was consumed. The crude reaction mixture waspartitioned between diethyl ether and HCl (0.1 N). The organic layer waswashed with brine and dried over sodium sulfate. Filtration andevaporation of solvents in vacuo yielded a crude material, which waspurified by silica gel chromatography to provide 4.16 g (55%) of thedesired product as an off-white solid. ¹H NMR (300 MHz, CDCl₃): δ=2.20(s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 7.01 (s, 1H) ppm; ¹⁹F NMR (282 MHz,CDCl₃): δ=−74 ppm.

6-Hydroxy-3-methyl-4-vinyl-phthalic acid dimethyl ester

To a solution of6-hydroxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethylester (2.17 g, 5.85 mmol) in N-methylpyrrolidinone (15 mL) was addedlithium chloride (743 mg, 17.5 mmol) and triphenylarsine (179 mg, 0.585mmol). Tributylvinyltin (2.04 g, 6.43 mmol) was added followed bytris(tribenzylideneacetone)dipalladium(0)-chloroform adduct (90 mg,0.087 mmol). The reaction was placed under an atmosphere of nitrogen andheated at 60° C. for 18 hours. The reaction was cooled to roomtemperature and poured onto a mixture of ice (20 g), EtOAc (40 mL), andpotassium fluoride (1 g). Stirring was continued for 1 hour. The aqueouslayer was extracted with EtOAc and the organic extracts filtered throughCelite. The combined organic layers were washed with water and driedover sodium sulfate. Filtration and evaporation of solvents in vacuoyielded a crude material, which was purified by silica gelchromatography to provide 1.27 g (87%) of the product as an off-whitesolid. ¹H NMR (300 MHz, CDCl₃): δ=2.16 (s, 3H), 3.91 (s, 3H), 3.92 (s,3H), 5.46 (dd, J=11.1, 1.2 Hz, 1H), 5.72 (dd, J=17.1, 0.9 Hz, 1H), 6.86(dd, J=17.1, 11.1 Hz, 1H), 7.14 (s, 1H), 10.79 (s, 1H) ppm.

4-Ethyl-6-hydroxy-3-methyl-phthalic acid dimethyl ester

6-Hydroxy-3-methyl-4-vinyl-phthalic acid dimethyl ester (1.27 g, 5.11mmol) was dissolved in benzene (10 mL) and EtOAc (10 mL).Tristriphenylphosphine rhodium chloride (150 mg) was added and thereaction was placed under an atmosphere of hydrogen. Stirring at roomtemperature was continued. After 14 hours, the solvents were removed invacuo and the crude material was purified by silica gel chromatographyto provide 1.14 g (88%) of the desired product as an off-white solid. ¹HNMR (300 MHz, CDCl₃): δ=1.19 (t, J=7.8 Hz, 3H), 2.10 (s, 3H), 2.60 (q,J=7.8 Hz, 2H), 3.89 (s, 6H), 6.87 (s, 1H), 10.79 (s, 1H) ppm.

1 6-Allyloxy-4-ethyl-3-methyl-phthalic acid dimethyl ester

4-Ethyl-6-hydroxy-3-methyl-phthalic acid dimethyl ester (1.01 g, 4.02mmol) was dissolved in DMF (5 mL). Potassium carbonate (3.33 g, 24.14mmol) was added, followed by allylbromide (2.92 g, 24.14 mmol). Thesuspension was heated at 60° C. After 14 hours, the reaction was cooledto room temperature and filtered. The solvents were removed in vacuo andthe crude material was purified by silica gel chromatography to provide0.976 g (83%) of the desired product as a colorless oil. ¹H NMR (300MHz, CDCl₃): δ=1.16 (t, J=7.2 Hz, 3H), 2.20 (s, 3H), 2.62 (q, J=7.2 Hz,2H), 3.83 (s, 3H), 3.84 (s, 3H), 4.57 (m, 2H), 5.26 (dd, J=9.3, 1.5 Hz,1H), 5.41 (dd, J=13.5, 1.5 Hz, 1H), 5.98 (m, 1H), 6.82 (s, 1H) ppm.

4-Allyl-5-ethyl-3-hydroxy-6-methyl-phthalic acid dimethyl ester

6-Allyloxy-4-ethyl-3-methyl-phthalic acid dimethyl ester (1.25 g, 4.28mmol) was heated at 21° C. under an atmosphere of nitrogen. After 14hours, the reaction was cooled to room temperature. The crude materialwas purified by silica gel chromatography to provide 0.971 g (77%) ofthe desired product as a colorless oil. ¹H NMR (300 MHz, CDCl₃): δ=1.14(t, J=7.8 Hz, 3H), 2.17 (s, 3H), 2.68 (q, J=7.8 Hz, 2H), 3.49 (m, 2H),3.86 (s, 3H), 3.89 (s, 3H), 4.89-5.01 (m, 2H), 5.93 (m, 1H), 11.22 (s,1H) ppm.

5 6-Allyl-5-ethyl-7-hydroxy-4-methyl-3H-isobenzofuran-1-one

4-Allyl-5-ethyl-3-hydroxy-6-methyl-phthalic acid dimethyl ester (0.971g, 3.32 mmol) was dissolved in MeOH (8 mL) at room temperature. Asolution of sodium hydroxide (0.798 g, 19.95 mmol) in water (10 mL) wasadded and the suspension was heated at 55° C. After 16 hours, thereaction was cooled to room temperature and washed with diethyl ether.The aqueous layer was acidified (1N HCl) and the suspension wasextracted with EtOAc. The combined organic layers were dried over sodiumsulfate. Filtration and evaporation of solvents in vacuo yielded thedesired bis acid as a white solid (0.846 g, 98%, M⁺=263). The bis acidwas dissolved in acetic acid (6 mL) and HCl (conc., 1.5 mL). Thereaction was heated at 80° C. Zn dust (0.635 g, 9.72 mmol, each) wasadded in portions every hour for 7 hours. Stirring at 80° C. wascontinued for additional 10 hours. The reaction was cooled to roomtemperature, and water was added. The resultant suspension was extractedwith EtOAc. The combined organic extracts were washed with sodiumbicarbonate solution and dried over sodium sulfate. Filtration andevaporation of solvents in vacuo yielded the crude product, which waspurified by silica gel chromatography to provide 0.375 g (50%) of theproduct as a white solid. ¹H NMR (300 MHz, CDCl₃): δ=1.14 (t, J=7.5 Hz,3H), 2.18 (s, 3H), 2.71 (q, J=7.5 Hz, 2H), 3.49 (m, 2H), 4.95 (d, J=17.1Hz, 1H), 5.02 (d, J=10.2 Hz, 1H), 5.23 (s, 2H), 5.98 (m, 1H), 7.66 (s,1H) ppm.

56-Allyl-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

To a solution of6-allyl-5-ethyl-7-hydroxy-4-methyl-3H-isobenzofuran-1-one (199 mg, 0.857mmol), PPh₃ (337 mg, 1.286 mmol), and 2-trimethylsilylethanol in THF (3mL) at 0° C. was added diisopropyl azodicarboxylate (259 mg, 1.286mmol). The resulting yellow solution was allowed to warm to roomtemperature and stirred for one hour. The solvent was removed in vacuoand the crude material was dissolved in diethyl ether (3 mL). Hexanes(1.5 mL) were added. Triphenylphosphine oxide was removed by filtrationand the filtrate was concentrated and purified by silica gelchromatography to provide the desired product (261 mg, 92%) as a clearoil. ¹H NMR (300 MHz, CDCl₃): δ=0.04 (s, 9H), 1.15 (t, J=7.8 Hz, 3H),1.25 (m, 2H), 2.20 (s, 3H), 2.73 (q, J=7.8 Hz, 2H), 3.54 (m, 2H), 4.28(m, 2H), 4.95 (d, J=17.1 Hz, 1H), 5.02 (d, J=10.2 Hz, 1H), 5.15 (s, 2H),5.95 (m, 1H) ppm.

[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde

A solution of6-allyl-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(261 mg, 0.788 mmol) in MeOH (5 mL), CH₂Cl₂ (5 mL) and pyridine (50 μL)was cooled to −78° C. using a dry ice/acetone bath according to theprocedure of Smith, D. B. et al., J. Org. Chem., 1996, 61, 6, 2236. Astream of ozone was bubbled through the reaction via a gas dispersiontube until the reaction became blue in color (15 minutes). The ozoneline was replaced with a stream of nitrogen and bubbling continued foranother 15 minutes, by which time the blue color had disappeared. Tothis solution, at −78° C., was added thiourea (59.9 mg, 0.788 mmol) inone portion, and the cooling bath was removed. The reaction was allowedto warn to room temperature and stirred for 15 hours. The reactionmixture was filtered and then partitioned between CH₂Cl₂ and water. Theaqueous layer was extracted with CH₂Cl₂ one more time and the organicextracts were combined, washed with aqueous 1N HCl, saturated NaHCO₃ andbrine and dried over sodium sulfate. Filtration and evaporation ofsolvents in vacuo yielded the crude product, which was purified bysilica gel chromatography to afford 181 mg (69%) of the product as awhite solid. ¹H NMR (300 MHz, CDCl₃): δ=0.04 (s, 9H), 1.11 (t, J=7.5 Hz,3H), 1.19 (m, 2H), 2.21 (s, 3H), 2.66 (q, J=7.5 Hz, 2H), 3.90 (s, 2H),4.36 (m, 2H), 5.18 (s, 2H), 9.71 (s, 1H) ppm.

4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal

[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde(90 mg, 0.269 mmol) and 2-(triphenyl-phosphorylidene)-propionaldehyde(72.9 mg, 0.23 mmol) in toluene (3 mL) were heated at 100° C. After 15hours, a second portion of 2-(triphenyl-phosphanylidene)-propionaldehyde(33 mg, 0.11 mmol) was added and the reaction mixture was heated foradditional 9 hours. The toluene was removed in vacuo, and the residuewas purified by silica gel chromatography to provide 77.6 mg (77%) ofthe desired product as a pale yellow oil. ¹H NMR (300 MHz, CDCl₃):δ=0.03 (s, 9H), 1.15 (t, J=7.5 Hz, 3H), 1.21 (m, 2H), 1.93 (s, 3H), 2.21(s, 3H), 2.71 (q, J=7.5 Hz, 2H), 3.82 (d, J=6.9 Hz, 2H), 4.34 (m, 2H),5.18 (s, 2H), 6.38 (m, 1H), 9.35 (s, 1H) ppm.

5-Ethyl-6-(4-hydroxy-3-methyl-but-2-enyl)-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(77.6 mg, 0.207 mmol) was dissolved in MeOH (4 mL). A solution of CeCl₃(51.1 mg, 0.207 mmol) in MeOH/water (9/1, 0.66 mL) was added and thesolution was cooled to 0° C. A solution of lithium borohydride in THF(2M, 0.105 mL) was added dropwise. After 15 minutes, the reaction wasquenched with 1N HCl (0.5 mL). The MeOH was removed in vacuo and thecrude material was partitioned between DCM and water. The aqueous layerwas extracted with DCM and the combined organic layers were washed withsodium bicarbonate solution and dried over sodium sulfate. Filtrationand evaporation of solvents yielded a crude oil, which was purified bysilica gel chromatography to provide 57.2 mg (73%) of the desiredproduct. ¹H NMR (300 MHz, CDCl₃): δ=0.04 (s, 9H), 1.15 (t, J=7.8 Hz,3H), 1.26 (m, 2H), 1.86 (s, 3H), 2.19 (s, 3H), 2.72 (q, J=7.8 Hz, 2H),3.52 (d, J=6.3 Hz, 2H), 3.99 (s, 2H), 4.34 (m, 2H), 5.14 (s, 2H), 5.32(m, 1H) ppm.

6-(4-Bromo-3-methyl-but-2-enyl)-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

5-Ethyl-6-(4-hydroxy-3-methyl-but-2-enyl)-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(57.2 mg, 0.152 mmol) was dissolved in DCM (3.5 mL). Polymer-boundtriphenylphosphine (3 mmol/g, 152.1 mg) was added and the mixture wasmechanically stirred at room temperature. Carbon tetrabromide (151.3 mg,0.456 mmol) was added and the solution was stirred at room temperature.After 2 hours, the reaction was filtered and the solvent was removed invacuo. The crude material was purified by silica gel chromatography toprovide 58.0 mg (87%) of the desired product. ¹H NMR (300 MHz, CDCl₃):δ=0.04 (s, 9H), 1.15 (t, J=7.8 Hz, 3H), 1.25 (m, 2H), 1.95 (s, 3H), 2.20(s, 3H), 2.70 (q, J=7.8 Hz, 2H), 3.52 (d, J=6.3 Hz, 2H), 3.94 (s, 2H),4.28 (m, 2H), 5.14 (s, 2H), 5.50 (m, 1H) ppm.

{4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid

A solution of4-[6′-ethyl-7′-methyl-3′-oxo-4′-(2″-trimethylsilanyl-ethoxy)-1′,3′-dihydro-isobenzofuran-5′-yl]-2-methyl-but-2-enylbromide (58 mg, 0.132 mmol) in trimethylphosphite (0.8 mL) was heated at110° C. After 2 hours the reaction was complete. The reaction was cooledto room temperature and the excess trimethylphosphite was removed invacuo. The crude material was used in the next step without furtherpurification.

The crude product of the Arbuzov reaction was dissolved in MeCN (0.8mL). Trimethylsilyl bromide (202.2 mg, 1.321 mmol) was added and thereaction was stirred at room temperature. After 15 minutes, lutidine(155.7 mg, 1.453 mmol) was added and stirring at room temperature wascontinued. After 2 hours, additional trimethylsilyl bromide (202.2 mg,1.321 mmol) was added and stirring at room temperature was continued.After 4 hours, the reaction was quenched with MeOH (2 mL). The solventswere evaporated in vacuo, and the crude material was purified by RP-HPLC(eluent: water/MeCN). The product-containing fractions were combined andlyophilized to yield 2.3 mg (5.1%) of the free phosphonic acid. ¹H NMR(300 MHz, DMSO-d6): δ=1.07 (t, J=7.5 Hz, 3H), 1.84 (s, 3H), 2.14 (s,3H), 2.64 (q, J=7.5 Hz, 2H), 3.34 (m, 4H), 5.06 (m, 1H), 5.25 (s, 2H)ppm; ³¹P NMR (121 MHz, DMSO-d6): δ=22.19 ppm; MS=341 [M⁺+1].

Example 318

Representative compounds of the invention can be prepared as illustratedbelow.

[2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal

[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde(90 mg, 0.269 mmol) and 2-(triphenyl-phosphorylidene)-butyraldehyde(98.4 mg, 0.296 mmol) in toluene (3 mL) were heated at 100° C. After 15hours, a second portion of 2-(triphenyl-phosphanylidene)-butyraldehyde(98.4 mg, 0.296 mmol) was added and the reaction mixture was heated foradditional 33 hours. After concentration, the residue was purified bysilica gel chromatography to provide 50.3 mg (48%) of the desiredproduct as a pale yellow oil.

5-Ethyl-6-(3-hydroxymethyl-pent-2-enyl)-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal(50.3 mg, 0.129 mmol) was dissolved in MeOH (3 mL). A solution of CeCl₃(31.9 mg, 0.129 mmol) in MeOH/water (9/1, 0.66 mL) was added and thesolution was cooled to 0° C. A solution of lithium borohydride in THF(2M, 0.065 mL) was added dropwise. After 10 minutes, the reaction wasquenched with 1N HCl (0.5 mL). The methanol was removed in vacuo and thecrude material was partitioned between DCM and water. The aqueous layerwas extracted with DCM and the combined organic layers were washed withsodium bicarbonate solution and were dried over sodium sulfate.Filtration and evaporation of solvents in vacuo yielded a crude oil,which was purified by silica gel chromatography to provide 35.4 mg (70%)of the desired product. ¹H NMR (300 MHz, CDCl₃): δ=0.04 (s, 9H),1.10-1.19 (m, 6H), 1.26 (m, 2H), 2.19 (s, 3H), 2.32 (q, J=7.5 Hz, 2H),2.72 (q, J=7.5 Hz, 2H), 3.54 (d, J=6.6 Hz, 2H), 4.05 (s, 2H), 4.26 (m,2H), 5.14 (s, 2H), 5.27 (m, 1H) ppm.

6-(3-Bromomethyl-pent-2-enyl)-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one

5-Ethyl-6-(3-hydroxymethyl-pent-2-enyl)-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(35.4 mg, 0.090 mmol) was dissolved in DCM (3.0 mL). Polymer-boundtriphenylphosphine (3 mmol/g, 90.7 mg) was added, and the mixture wasmechanically stirred at room temperature. Carbon tetrabromide (90.2 mg,0.272 mmol) was added and the solution was stirred at room temperature.After 2 hours, the reaction was filtered and the solvent was removed invacuo. The crude material was purified by silica gel chromatography toprovide 32.0 mg (78%) of the desired product. The material was used inthe next step without further characterization.

[2-Ethyl-4-(6-ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-but-2-enyl]-phosphonicacid

A solution of6-(3-bromomethyl-pent-2-enyl)-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(32 mg, 0.070 mmol) in trimethylphosphite (0.8 mL) was heated at 110° C.After 2 hours, the reaction was complete. The reaction was cooled toroom temperature and the excess trimethylphosphite was removed in vacuo.The crude material was used in the next step without furtherpurification.

The crude product of the Arbuzov reaction was dissolved in MeCN (0.8mL). Trimethylsilyl bromide (108.0 mg, 0.706 mmol) was added and thereaction was stirred at room temperature. After 2 hours, a second batchof trimethysilyl bromide (108.0 mg, 0.706 mmol) was added. After 3hours, the reaction was quenched with MeOH (2 mL). The solvents wereevaporated in vacuo and the crude material was purified by RP-HPLC(eluent: water/MeCN). The product-containing fractions were combined andlyophilized to yield 15.7 mg (63%) of the product. ¹H NMR (300 MHz,DMSO-d6): ∂=0.98-1.09 (m, 6H), 2.10 (s, 3H), 2.30 (m, 2H), 2.64 (q,J=7.5 Hz, 2H), 3.38 (m, 4H), 5.03 (m, 1H), 5.25 (s, 2H) ppm; ³¹P NMR(121 MHz, DMSO-d6): δ=22.26 ppm; MS=355 [M⁺+1].

Example 319

Representative compounds of the invention can be prepared as illustratedbelow.

(2-{4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester

4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(19.7 mg, 0.052 mmol) and aminoethylphosphonic acid diethylester oxalatesalt (15.6 mg, 0.057 mmol) were dissolved in DMF (0.5 mL). Acetic acid(15.7 mg, 0.263 mmol) was added, followed by sodiumtriacetoxyborohydride (22.3 mg, 0.105 mmol). After 4 hours, the crudereaction mixture was purified by RP-HPLC (eluent: water/MeCN) to provide27.7 mg (97%) of the desired product after lyophilization. ¹H NMR (300MHz, CDCl₃): δ=0.04 (s, 9H), 1.14 (t, J=7.5 Hz, 3H), 1.26 (m, 2H), 1.30(t, J=7.2 Hz, 6H), 1.95 (s, 3H), 2.19 (s, 3H), 2.23 (m, 2H), 2.68 (q,J=7.5 Hz, 2H), 3.18 (m, 2H), 3.53 (s, 2H), 4.13 (m, 4H), 4.28 (m, 2H),5.15 (s, 2H), 5.51 (m, 1H) ppm; ³¹P NMR (121 MHz, CDCl₃): δ=27.39 ppm;MS=540 [M⁺+1].

{2-[4-(6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl}-phosphonicacid

(2-{4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester (27.7 mg, 0.051 mmol) was dissolved in DMF (0.5 mL)and DCM (0.5 mL). Trimethylsilyl bromide (78.3 mg, 0.512 mmol) was addedand the reaction was stirred at room temperature. After 20 hours, thereaction was quenched with MeOH (0.3 mL). The solvents were evaporatedin vacuo and the crude material was purified by RP-HPLC (eluent:water/MeCN). The product-containing fractions were combined andlyophilized to yield 14.2 mg (57%) of the free phosphonic acid [MS: 484M⁺+1].

The material was dissolved in DCM (0.5 mL). TFA (0.05 mL) was added andstirring at room temperature was continued. After 20 minutes, thesolvents were removed in vacuo and the crude material was purified byRP-HPLC (eluent: water/MeCN*0.1% TFA). The product-containing fractionswere combined and lyophilized to yield 7.6 mg (52%) of the product asthe TFA salt. ¹H NMR (300 MHz, DMSO-d6): δ=1.07 (t, J=7.5 Hz, 3H), 1.84(s, 3H), 1.90 (m, 2H), 2.11 (s, 3H), 2.63 (q, J=7.5 Hz, 2H), 2.99 (m,2H), 3.43 (d, J=6.3 Hz, 2H), 3.51 (s, 2H), 5.26 (s, 2H), 5.45 (m, 1H)ppm; ³¹P NMR (121 MHz, DMSO-d6): δ=20.02 ppm; MS 384 [M⁺+1].

(2-{2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enylamino}-ethyl)-phosphonicacid diethyl ester

2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal(26.6 mg, 0.068 mmol) and aminoethylphosphonic acid diethylester oxalatesalt (20.4 mg, 0.075 mmol) were dissolved in DMF (0.8 mL). Acetic acid(20.5 mg, 0.342 mmol) was added, followed by sodiumtriacetoxyborohydride (27.6 mg, 0.137 mmol). After 8 hours, the crudereaction mixture was purified by RP-HPLC (eluent: water/MeCN) to provide24.9 mg (65%) of the desired product after lyophilization. ¹H NMR (300MHz, CDCl₃): δ=0.05 (s, 9H), 1.10-1.24 (m, 8H), 1.35 (t, J=7.5 Hz, 6H),2.19 (s, 3H), 2.23 (m, 2H), 2.35 (q, J=7.8 Hz, 2H), 2.70 (q, J=7.2 Hz,2H), 3.25 (m, 2H), 3.56 (m, 4H), 4.15 (m, 4H), 4.29 (m, 2H), 5.15 (s,2H), 5.47 (m, 1H) ppm; ³¹P NMR (121 MHz, CDCl₃): δ=27.71 ppm; MS=554[M⁺+1].

{2-[2-Ethyl-4-(6-ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-but-2-enylamino]-ethyl}-phosphonicacid

(2-{2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (24.9 mg, 0.045 mmol) wasdissolved in DMF (0.5 mL) and DCM (0.5 mL). Trimethylsilyl bromide (68.7mg, 0.449 mmol) was added and the reaction was stirred at roomtemperature. After 20 hours, the reaction was quenched with MeOH (0.15mL). The solvents were evaporated in vacuo and the crude material waspurified by RP-HPLC (eluent: water/MeCN). The product-containingfractions were combined and lyophilized to yield 8.0 mg of the freephosphonic acid [MS: 498 M⁺+1].

This material was dissolved in DCM (0.5 mL). TFA (0.05 mL) was added,and stirring at room temperature was continued. After 20 minutes, thesolvents were removed in vacuo and the crude material was purified byRP-HPLC (eluent: water/MeCN*0.1% TFA). The product-containing fractionswere combined and lyophilized to yield 4.4 mg (54%) of the product asthe TFA salt. ¹H NMR (300 MHz, DMSO-d6): δ 1.05 (m, 6H), 1.60 (m, 2H),2.10 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 2.63 (q, J=6.9 Hz, 2H), 2.93 (m,2H), 3.45 (m, 4H), 5.24 (s, 2H), 5.36 (m, 1H) ppm.; ³¹P NMR (121 MHz,DMSO-d6): δ=16.93 ppm; MS=398 [M⁺+1].

Example 320

Representative compounds of the invention can be prepared as illustratedbelow.

2-({4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phenoxy-phosphinoylamino)-propionicacid ethyl ester

4-[6′-ethyl-7′-methyl-3′-oxo-4′-(2″-trimethylsilanyl-ethoxy)-1′,3′-dihydro-isobenzofuran-5′-yl]-2-methyl-but-2-en-phosphonicacid (44.8 mg, 0.101 mmol), dicyclohexylcarbodiimide (52.6 mg, 0.254mmol), and phenol (95.8 mg, 1.018 mmol) were dissolved in pyridine (0.3mL) and heated at 70° C. for 4 hours. The reaction mixture was cooled toroom temperature and the pyridine was removed in vacuo. The crudematerial was partitioned between DCM and HCl (0.1N). The aqueous layerwas extracted with DCM and the combined organic layers were dried oversodium sulfate. Filtration and evaporation of solvents in vacuo yieldeda crude material, which was used in the next step without furtherpurification.

The crude material was dissolved in MeCN (0.8 mL) and water (0.3 mL).Aqueous sodium hydroxide solution (2N, 0.8 mL) was added in portions(0.2 mL). After all starting material was consumed, the organic solventwas removed in vacuo and the crude material was partitioned betweenchloroform and aqueous HCl (1N). The aqueous layer was extracted withchloroform. The combined organic layers were dried over sodium sulfate.Filtration and evaporation of solvents yielded the crude product as amixture of mono phenyl ester and the symmetrical anhydride.

The crude material of the previous step and ethyl (L)-alaninehydrochloride salt (78.1 mg, 0.509 mmol) were dissolved in DMF (0.4 mL).DMAP (1.2 mg, catalytic) was added, followed by diisopropylethylamine(131.3 mg, 1.018 mmol). Stirring at room temperature was continued.After 20 minutes, complete conversion of the anhydride was observed.After 2 hours, PyBOP (101 mg, 0.202 mmol) was added and stirring at roomtemperature was continued. The reaction was filtered and the crudereaction solution was purified by RP-HPLC (eluent: water/MeCN). Theproduct-containing fractions were combined and lyophilized to yield theproduct (15.7 mg, 25% over three steps) as a white powder. ¹H NMR (300MHz, CDCl₃): δ=0.03 (s, 9H), 1.13-1.28 (m, 8H), 2.03 (s, 3H), 2.19 (s,3H), 2.62-2.74 (m, 4H), 3.38 (m, 1H), 3.53 (t, J=6.3 Hz, 2H), 4.03 (m,3H), 4.30 (m, 2H), 5.14 (s, 2H), 5.31 (m, 1H), 7.11-7.17 (m, 3H),7.25-7.30 (m, 2H) ppm; ³¹P NMR (121 MHz, CDCl₃): δ=27.04, 27.73 ppm;MS=615 [M⁺+1].

2-{[4-(6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phenoxy-phosphinoylamino}-propionicacid ethyl ester

2-({4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phenoxy-phosphinoylamino)-propionicacid ethyl ester (7.5 mg, 0.012 mmol) was dissolved in TFA/DCM (10%, 0.3mL) at −20° C. The reaction mixture was warmed to 0° C. and stirred atthis temperature for 45 minutes. Pyridine (0.09 mL) was added thesolvents were removed in vacuo. The crude material was purified byRP-HPLC (eluent: water/MeCN). The product-containing fractions werecombined and lyophilized, yielding a white powder (5.5 mg, 87%). ¹H NMR(300 MHz, CDCl₃): δ=1.12-1.29 (m, 6H), 2.03 (s, 3H), 2.17 (s, 3H),2.65-2.74 (m, 4H), 3.38 (m, 1H), 3.53 (t, J=6.3 Hz, 2H), 4.03 (m, 3H),5.22 (s, 2H), 5.36 (m, 1H), 7.11-7.16 (m, 3H), 7.24-7.30 (m, 2H), 7.72(m, 1H) ppm; ³¹P NMR (121 MHz, CDCl₃): δ=27.11, 27.57 ppm; MS=515[M⁺+1].

Example 321

Representative compounds of the invention can be prepared as illustratedbelow.

6-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid

A mixture of6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester (1.5 g, 3.45 mmol) and sodium hydroxide (552 mg) in amixture of methanol (20 mL) and water (7 mL) was stirred at roomtemperature for one hour. The solution was acidified with 1N HCl. Theprecipitate was collected by suction filtration and washed with water togive the desired product (1.2 g, 83%). ¹H NMR (300 MHz, CDCl₃) δ 0.02(s, 9H), 1.15-1.22 (m, 2H), 1.76 (s, 3H), 2.13 (s, 3H), 2.12-2.28 (m,2H), 2.35-2.41 (m, 2H), 3.37 (d, 2H, J=7 Hz), 3.71 (s, 3H), 4.22-4.28(m, 2H), 5.07 (s, 2H), 5.13-5.17 (m, 1H) ppm; MS (m/z) 419.3 [M−H]⁻,443.2 [M+Na]⁺.

({6-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoylamino}-methyl)-phosphonicacid diethyl ester

To a solution of6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid (50 mg, 0.12 mmol) in THF (1 mL) was added isobutyl chloroformate(17 μL, 0.13 mmol) and triethylamine (50 μL, 0.36 mmol) at 0° C. Afterstirring at 0° C. for 2 hours, diethyl (aminomethyl) phosphonate oxalate(62 mg, 0.26 mmol) was added and stirring was continued at roomtemperature for 20 minutes. After removal of solvent, the residue waspurified by preparative reverse-phase HPLC to afford 54.8 mg (81%) ofthe desired product. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 1.15-1.22(m, 2H), 1.31 (t, 6H), 1.81 (s, 3H), 2.18 (s, 3H), 2.30 (m, 4H), 3.41(d, 2H, J=7 Hz), 3.65 (dd, 2H, J=6, 12 Hz), 3.77 (s, 3H), 3.77-4.16 (m,4H), 4.26-4.32 (m, 2H), 5.12 (s, 2H), 5.17-5.19 (m, 1H), 5.86 (bs, 1H)ppm; ³¹P (121.4 MHz, CDCl₃) δ 23.01 ppm; MS (m/z) 568 [M−H]⁻, 592[M+Na]⁺.

{[6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoylamino]-methyl}-phosphonicacid

To a solution of({6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoylamino}-methyl)-phosphonic acid diethyl ester (40 mg, 0.07 mmol) inacetonitrile (1 mL) was added TMSBr (91 μL, 0.7 mmol) followed by2,6-lutidine (81.5 μL, 0.7 mmol). The reaction was allowed to proceedovernight when it was completed as judged by LCMS. The reaction mixturewas quenched with MeOH and concentrated to dryness. The residue waspurified by preparative reverse-phase HPLC to afford 2.6 mg (9%) ofdesired product as a white solid. ¹H NMR (300 MHz, CD₃OD) δ 1.67 (s,3H), 2.17 (m, 5H), 2.30-2.46 (m, 2H), 2.80-2.86 (m, 2H), 3.55 (m, 2H),3.82 (s, 3H), 5.26 (s, 3H) ppm; ³¹P (121.4 MHz, CD₃OD) δ 10.27 ppm; MS(m/z) 412 [M−H]⁻, 414 [M+H]⁺.

Example 322

Representative compounds of the invention can be prepared as illustratedbelow.

(2-{6-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoylamino}-ethyl)-phosphonicacid diethyl ester

To a solution of6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid (50 mg, 0.12 mmol) in THF (1 mL) was added isobutyl chloroformate(17 μL, 0.13 mmol) and triethylamine (50 μL, 0.36 mmol) at 0° C. Afterstirring at 0° C. for 2 hours, diethyl (aminoethyl) phosphonate oxalate(62 mg, 0.26 mmol) was added and stirred at room temperature wascontinued for one hour. After removal of solvent, the residue waspurified by preparative reverse-phase HPLC to afford 37 mg (54%) of thedesired product as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s,9H), 1.15-1.22 (m, 2H), 1.31 (t, 6H), 1.81 (s, 3H), 1.85-1.93 (m, 2H),2.18 (s, 3H), 2.30 (m, 4H), 3.41 (d, 2H, J=7 Hz), 3.48-3.54 (m, 2H),3.77 (s, 3H), 3.77-4.16 (m, 4H), 4.26-4.32 (m, 2H), 5.12 (s, 2H),5.17-5.19 (m, 1H), 6.30 (bs, 1H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 29.91ppm; MS (m/z) 584 [M+H]⁺.

{2-[6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoylamino]-ethyl}-phosphonicacid

To a solution of(2-{6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoylamino}-ethyl)-phosphonicacid diethyl ester (36.6 mg, 0.063 mmol) in acetonitrile (1 mL) wasadded TMSBr (81 μL, 0.63 mmol) followed by 2,6-lutidine (73 μL, 0.63mmol). The reaction was allowed to proceed overnight, when it wascompleted as judged by LCMS. The reaction mixture was quenched with MeOHand concentrated to dryness. The residue was purified by preparativereverse-phase HPLC to afford 5.8 mg (29%) of desired product as a whitesolid. ¹H NMR (300 MHz, CD₃OD) δ 1.80 (s, 3H), 2.14 (m, 5H), 2.25 (m,4H), 3.35 (m, 2H), 3.38-3.38 (m, 2H), 3.75 (s, 3H), 5.23 (s, 3H) ppm;³¹P (121.4 MHz, CD₃OD) δ 26.03 ppm; MS (m/z) 426 [M−H]⁻, 428 [M+H]⁺.

Example 323

Representative compounds of the invention can be prepared as illustratedbelow.

{4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid diphenyl ester

To a solution of[{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid (260 mg, 0.59 mmol) in DMF (6 mL) and phenol (555 mg, 5.9 mmol) wasadded dicyclohexyl carbodiimide (1.21 g, 5.9 mmol) and DMAP (36 mg,0.295 mmol). The reaction mixture was heated to 140° C. for 30 minutes.After cooling to room temperature, the mixture was partitioned betweenEtOAc/Hexane (1:1) and 5% aqueous LiCl solution. The organic layer waswashed with 5% aqueous LiCl solution repeatedly, then dried over Na₂SO₄.After removal of solvent, the residue was purified by silica gelchromatography to provide 75 mg (21%) of the desired product. MS (m/z)617 [M+Na]⁺.

{4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid monophenyl ester

To a solution of{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid diphenyl ester (75 mg, 0.126 mmol) in THF (5 mL) was added 1N NaOH(0.1 mL) solution. The mixture was allowed to stir at room temperaturefor 16 hours. EtOAc was added and the resulting mixture was washed with1H HCl. The organic layer was concentrated to dryness and the residuewas purified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 24.8 mg (38%) of the desiredproduct. MS (m/z) 517 [M−H]⁻, 541 [M+Na]⁺.

2-({4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phenoxy-phosphinoyloxy)-propionicacid ethyl ester

To a solution of{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid monophenyl ester (25 mg, 0.048 mmol) and ethyl (S)-(−)-lactate (34mg, 0.288 mmol) in pyridine (1 mL) was added PyBOP (125 mg, 0.24 mmol).The solution was stirred at room temperature for 16 hours andconcentrated. The residue was purified by RP HPLC using a C18 columnwith a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 24 mg(83%) of the desired product. MS (m/z) 641 [M+Na]⁺.

2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phenoxy-phosphinoyloxy}-propionicacid ethyl ester

To a solution of2-({4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phenoxy-phosphinoyloxy)-propionicacid ethyl ester (24 mg, 0.039 mmol) in DCM (1 mL) was added TFA (0.5mL) and the mixture was stirred at room temperature for 10 minutes. Thereaction mixture was dried under reduced pressure and the residue waspurified by RP-HPLC to provide 18 mg (90%) of the desired product as aclear oil. ¹H NMR (300 MHz, CDCl₃) δ 1.18-1.34 (m, 3H), 1.36-1.48 (dd,3H), 2.02 (m, 3H), 2.17 (s, 3H), 2.78-2.98 (dd, 2H), 3.45 (m, 2H), 3.79(s, 3H), 4.05-4.25 (m, 2H), 4.97 (m, 1H), 5.21 (s, 2H), 5.48 (t, J=7.2Hz, 1H), 7.05-7.18 (m, 5H) ppm; ³¹P (121.4 MHz, CDCl₃) δ 24.59, 26.13ppm; MS (m/z) 517 [M−H]⁻, 519 [M+H]⁺.

Example 324

Representative compounds of the invention can be prepared as illustratedbelow.

2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phenoxy-phosphinoyloxy}-propionicacid

To a solution of2-{[4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phenoxy-phosphinoyloxy}-propionicacid ethyl ester (10 mg, 0.019 mmol) in THF (3 mL) was added 1N NaOH(232 μL), and the mixture was stirred at room temperature for 1 hour.The reaction mixture was dried under reduced pressure and the residuewas purified by RP-HPLC to provide 6 mg (77%) of the desired product asa clear oil. ¹H NMR (300 MHz, CD₃OD) δ 1.41 (d, J=7 Hz, 3H), 1.97 (s,3H), 2.16 (s, 3H), 2.59 (d, J=22 Hz, 2H), 3.45 (m, 2H), 3.79 (s, 3H),4.83 (m, 1H), 5.26 (s, 2H), 5.43 (t, J=7.2 Hz, 1H) ppm; ³¹P (121.4 MHz,CD₃OD) δ 27.02 ppm; MS (m/z) 413 [M−H]⁻, 415 [M+H]⁺.

Example 325

Representative compounds of the invention can be prepared as illustratedbelow.

2-{[4-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyl]-phenoxy-phosphinoylamino}-propionicacid ethyl ester

{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonicacid monophenyl ester (1 g, ˜1.9 mmol) was combined with pyBOP (2 g, 4mmol) and DMAP (120 mg, 0.96 mmol). A solution of L-alanine ethyl esterhydrochloride salt (2.9 g, 19 mmol) and diisopropylethylamine (6.7 mL,38 mmol) in pyridine (5 mL) was added to the monoacid mixture and thereaction was stirred at room temperature for 12 hours. The reactionmixture was then concentrated and purified twice by columnchromatography (1% MeOH/CH₂Cl₂ 3% MeOH/CH₂Cl₂). The resulting oil wasdissolved in a vigorously-stirred solution of 10% TFA/CH₂Cl₂ (30 mL) at−40° C. The reaction was gradually warmed to 0° C. After about 3 hours,the reaction was complete. Pyridine (4.5 mL) was added, and the reactionmixture was concentrated. The product was purified by preparative TLC(5% MeOH/CH₂Cl₂) and concentrated to give 210 mg (21%) of the desiredproduct as a light yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.83-7.70 (m,1H), 7.30-7.20 (m, 2H), 7.18-7.03 (m, 3H), 5.60-5.35 (m, 1H), 5.21 (s,2H), 4.17-3.95 (m, 3H), 3.79 (s, 3H), 3.60-3.40 (m, 3H), 2.80-2.60 (m,2H), 2.17 (m, 3H), 2.01 (m, 3H), 1.30-1.10 (m, 6H) ppm; ³¹P NMR (121MHz, CDCl₃) δ 28.0, 27.5 ppm; MS (m/z) 516 [M−H]⁻.

Example 326

Representative compounds of the invention can be prepared as illustratedbelow.

2-(Dimethoxy-phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid methyl ester

To a solution of trimethylphosphonoacetate (63 μL, 0.39 mmol) in THF (1mL) was added NaN(TMS)₂ (0.39 mmol, 0.39 mL) at ambient temperature.After 30 minutes, a solution of6-(4-bromo-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(69 mg, 0.156 mmol) in THF (1 mL) was added. The reaction mixture wasstirred for 2 hours, when a precipitate was observed. The reactionmixture was worked up by addition of a saturated aqueous solution ofammonium chloride and extraction of the product with EtOAc. The organicextract was dried and the product was purified using silica gelchromatography with 0-100% EtOAc-Hexanes to provide 40 mg of the desiredproduct as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 0.05 (s, 9H),1.20-1.26 (m, 2H), 1.79 (s, 3H), 2.17 (s, 3H), 2.42-2.72 (m, 2H), 3.19(ddd, 1H, J=4, 12, 23 Hz), 3.39 (d, 2H, J=7 Hz), 3.62 (s, 3H), 3.75 (s,3H), 3.77-3.84 (m, 6H), 4.27-4.34 (m, 2H), 5.12 (s, 2H), 5.24 (t, 1H,J=7 Hz) ppm; ³¹P (121.4 MHz, CDCl₃) δ 25.1 ppm; MS (m/z) 565.2 [M+Na]⁺.

6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-2-phosphono-hex-4-enoicacid methyl ester

To a solution of2-(dimethoxy-phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester (30 mg, 0.055 mmol) in acetonitrile (2 mL) was addedtrimethylsilyl bromide (0.18 mL). After 10 minutes, 2,6-lutidine (0.16mL) was added to the reaction at ambient temperature. The reaction wasallowed to proceed for 16 hours before it was concentrated to dryness.The residue was resuspended in a solution of DMF: H₂O (8:2, 1 mL) andpurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 18 mg of the product as a whitepowder. ¹H NMR (300 MHz, CD₃OD) δ 1.81 (s, 3H), 2.16 (s, 3H), 2.40-2.49(m, 1H), 2.63 (dt, 1H, J=6, 17 Hz), 3.07 (ddd, 1H, J=4, 12, 23 Hz), 3.38(3, 2H, J=7 Hz), 3.52 (s, 3H), 3.77 (s, 3H), 5.25 (s, 2H), 5.28 (t, 1H,J=7 Hz) ppm; ³¹P (121.4 MHz, CDCl₃) δ 19.5 ppm; MS (m/z) 415.2 [M+H]⁺,437.2 [M+Na]⁺.

Example 327

Representative compounds of the invention can be prepared as illustratedbelow.

2-(Bis-(2,2,2-trifluoroethoxy)phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester

To a solution of [bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acidmethyl ester (186 μL, 0.88 mmol) in anhydrous THF (2 mL) was added asolution of 1N NaN(TMS)₂ in THF (0.88 mL, 0.88 mmol). The solution wasstirred at room temperature for 30 minutes, whereupon a solution of6-(4-bromo-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(98 mg, 0.22 mmol) in THF (1 mL) was added. The reaction mixture wasstirred overnight when a precipitate was observed. The reaction mixturewas worked up by addition of a saturated aqueous solution of ammoniumchloride and extraction of the product with EtOAc. The organic extractwas dried and the product was purified by RP HPLC using a C18 columnwith a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 72 mg(48%) of the product as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 0.05(s, 9H), 1.22 (t, 3H, J=7 Hz), 1.81 (s, 3H), 2.18 (s, 3H), 2.5-2.7 (m,2H), 3.3 (ddd, 1H, J=4, 12, 23 Hz), 3.40 (d, 2H, J=7 Hz), 3.65 (s, 3H),3.76 (s, 3H), 4.29-5.13 (m, 6H), 5.13 (s, 2H), 5.28 (t, 1H, J=7 Hz) ppm;MS (m/z) 701.2 [M+Na]⁺.

2-(Bis-(2,2,2-trifluoroethoxy)phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-hydroxyoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester

[2-(Bis-(2,2,2-trifluoroethoxy)phosphoryl)-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid methyl ester (70 mg) was dissolved in a solution of 10%trifluoroacetic acid in dichloromethane (5 mL). After 10 minutes, themixture was concentrated and the product was purified by RP HPLC using aC18 column with a gradient of H₂O, 0.1% TFA-acetonitrile, 0.1% TFA toprovide 45 mg (75%) of the product as a colorless oil. ¹H NMR (300 MHz,CDCl₃) δ 1.81 (s, 3H), 2.16 (s, 3H), 2.5-2.7 (m, 2H), 3.3 (ddd, 1H),3.38 (d, 2H, J=7 Hz), 3.65 (s, 3H), 3.77 (s, 3H), 4.33-4.43 (m, 4H),5.21 (s, 2H), 5.33 (t, 1H, J=7 Hz) ppm; ³¹P (121.4 MHz, CDCl₃) δ 25.8ppm; MS (m/z) 601.2 [M+Na]⁺.

Example 328

Representative compounds of the invention can be prepared as illustratedbelow.

6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-[hydroxy-(2,2,2-trifluoro-ethoxy)-phosphoryl]-4-methyl-hex-4-enoicacid

To a solution of [bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acidmethyl ester (186 μL, 0.88 mmol) in anhydrous THF (0.5 mL) was added asolution of 1N NaOH (aqueous; 0.06 mL) and N-methylpyrrolidinone (0.2mL). After 6.5 hours, another aliquot of 1N NaOH (0.06 mL) was added andthe mixture was stirred overnight. After concentration, the residue wassuspended in DMF (<1 mL), neutralized with a few drops of TFA andpurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, 0.1% TFA to provide 5.6 mg (72%) of the product as awhite powder after lyophilization. ¹H NMR (300 MHz, CD₃OD) δ 1.83 (s,3H), 2.16 (s, 3H), 2.43-2.51 (m, 1H), 2.59-2.70 (m, 1H), 3.13 (ddd, 1H),3.40 (d, 2H), 3.76 (s, 3H), 4.36-4.47 (m, 2H), 5.25 (s, 2H), 5.34 (t,1H, J=7 Hz) ppm; MS (m/z) 505.2 [M+Na]⁺.

Example 329

Representative compounds of the invention can be prepared as illustratedbelow.

Phosphorous acidmono-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}ester

To a solution of6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one(75 mg, 0.20 mmol) and DIEA (49 μL, 0.28 mmol) in dioxane (2 mL) wasadded 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (56.7 mg, 0.28 mmol)according the procedure of Shadid, B. et al., Tetrahedron, 1989, 45, 12,3889. After 10 minutes, another portion of2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one (40 mg, 0.20 mmol) and DIEA(35 μL, 0.20 mmol) were added. The reaction was allowed to proceed atroom temperature for an additional hour, after which it was quenched bythe addition of H₂O. The solution was stirred for another 10 minutes andconcentrated in vacuo to a small volume. The product was triturated withdiethyl ether and coevaporated from acetonitrile (4×10 mL) to providethe product. ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 1.08-1.30 (m, 2H),1.84 (br s, 3H), 2.17 (s, 3H), 3.46 (br s, 2H), 3.76 (s, 3H), 4.21-4.39(m, 4H), 5.12 (s, 2H), 5.43-5.60 (m, 1H), 7.83 (br s, 1H); ³¹P (121.4MHz, CDCl₃) δ 7.22; MS (m/z) 441 [M−H]⁻.

Example 330

Representative compounds of the invention can be prepared as illustratedbelow.

Phosphoric acidmono-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}ester

A solution of phosphorous acidmono-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}ester(27 mg, 0.06 mmol) in dioxane (1 mL) was stirred with DIEA (21 μL, 0.12mmol) and N,O-bis(trimethylsilyl)acetamide (29 μL, 0.12 mmol) at roomtemperature for 3 hours. To the reaction solution was added2,2′-dipyridyldisulfide (16 mg, 0.072 mmol) and the mixture was allowedto stir for an additional 2 hours at room temperature. The reactionmixture was diluted by addition of H₂O and the solution was stirred for2 more hours when it was concentrated. The residue was dissolved in asolution of 10% TFA/CH₂Cl₂ and stirred at room temperature for 9 hours.The reaction mixture was dried under reduced pressure and the productwas purified by reverse-phase HPLC to provide the desired product as awhite solid. ¹H NMR (300 MHz, CD₃OD) δ 1.87 (s, 3H), 2.16 (s, 3H), 3.47(d, 2H, J=7 Hz), 3.79 (s, 3H), 4.28 (d, 2H, J=6 Hz), 5.26 (s, 2H),5.50-5.61 (m, 1H); ³¹P (121.4 MHz, CD₃OD) δ 0.50; MS (m/z) 357 [M−H]⁻.

Example 331

Several compounds of the invention are presented below.

Example 332

Additional representative compounds of the invention, and intermediatesthereof, can be prepared according to the methods presented below.

Synthesis of Phenacetaldehydes with Variants at R₁, R₂

The parent compound (R₁═OMe; R₂=Me) is accessible by semi-synthesis frommycophenolic acid as follows:

To a solution of mycophenolic acid (500 g, 1.56 mol) in MeOH (4 L) undernitrogen atmosphere was added sulfuric acid (10 mL) dropwise, and thesuspension was stirred at room temperature. After 2 hours, the reactionbecame homogeneous, and soon thereafter a precipitate was formed. Thereaction was allowed to stir at room temperature for 10 hours, at whichtime TLC indicated complete reaction. The reaction was cooled in an icebath to 10° C. and then filtered using a Buchner funnel. The filter cakewas washed with ice cold methanol (750 mL) followed by hexanes (750 mL)and then dried to give 497 g (95%) of the desired product as a solid: ¹HNMR (300 MHz, CDCl₃) 8, 1.81 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H),2.37-2.50 (m, 4H), 3.38 (d, 2H, J=7 Hz), 3.62 (s, 3H), 3.77 (s, 3H),5.13 (s, 2H), 5.22 (m, 1H), 7.17 (s, 1H).

To a solution (3.99 g, 11.9 mmol), PPh₃ (4.68 g, 17.9 mmol), anddiisopropyl azodicarboxylate (3.46 mL, 17.9 mmol) in THF (60 mL) at 0°C. was added a solution of 2-trimethylsilylethanol (2.05 mL, 14.3 mmol)in THF (20 mL). The resulting yellow solution was allowed to warm toroom temperature and stirred for 4 hours. The reaction was worked up byconcentrating the solution to dryness and addition of ether and hexanes.Triphenylphosphine oxide was removed by filtration and the filtrate wasconcentrated and purified by silica gel chromatography to provide 4.8 g(100%) as a clear oil: ¹H NMR (300 MHz, CDCl₃) δ 0.03 (s, 9H), 1.18-1.30(m, 2H), 1.81 (s, 3H), 2.18 (s, 3H), 2.25-2.33 (m, 2H), 2.37-2.45 (m,2H), 3.42 (d, 2H, J=7 Hz), 3.62 (s, 3H), 3.77 (s, 3H), 4.25-4.35 (m,2H), 5.13 (s, 2H), 5.12-5.22 (m, 1H).

A solution (9.6 g, 22 mmol) in MeOH (90 mL), CH₂Cl₂ (90 mL) and pyridine(0.7 mL) was cooled to −70° C. using a dry ice/acetone bath. A stream ofozone was bubbled through the reaction via a gas dispersion tube untilthe reaction became blue in color (1.5 hours). The ozone line wasreplaced with a stream of nitrogen and bubbling continued for another 30minutes, by which time the blue color had disappeared. To this solutionat −70° C. was added thiourea (1.2 g, 15.4 mmol) in one portion, and thecooling bath was removed. The reaction was allowed to warm to roomtemperature and stirred for 15 hours. The reaction was worked up byfiltration to remove solid thiourea S-dioxide, and then partitionedbetween CH₂Cl₂ and water. The organic layer was removed. The aqueouslayer was washed with CH₂Cl₂ and the organic extracts were combined,washed with aqueous 1N HCl, saturated NaHCO₃ and brine, and dried invacuo. The residue was purified by silica gel chromatography to afford7.3 g (99%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ −0.01 (s, 9H),1.05-1.15 (m, 2H), 2.15 (s, 3H), 3.69 (s, 3H), 3.78 (d, 2H, J=1 Hz),4.27-4.39 (m, 2H), 5.11 (s, 2H), 9.72 (d, 1H, J=1 Hz).

R₁ Variants

The starting material, synthesized according to J. Med. Chem., 1996, 39,4181-4196, is transformed to the desired aldehyde using methodsanalogous to those described above.

The starting material, synthesized according to J. Med. Chem., 1996, 39,4181-4196, is transformed to the desired aldehyde using methodsanalogous to those described above.

The starting material, synthesized according to J. Med. Chem., 1996, 39,4181-4196, is transformed to the desired aldehyde using methodsanalogous to those described above.

The aldehyde is dissolved in an organic solvent such as methanol andsodium borohydride is added. At the end of the reaction, aqueous HClsolution is added and the solvent is removed in vacuo. Furtherpurification is achieved by chromatography.

The resulting alcohol is dissolved in an organic solvent such asdichloromethane (DCM). Pyridine and acetic anhydride are added andstirring at room temperature is continued. At the end of the reactionadditional DCM is added and the solution is washed with aqueous HClsolution, aqueous sodium bicarbonate solution, and dried over sodiumsulfate. Filtration and evaporation of the solvent in vacuo gives thecrude product. Further purification is achieved by chromatography.

The acetate is dissolved in DCM and bromine is added, according to aprocedure from J. Med. Chem., 1996, 39, 4181-4196. At the end of thereaction, additional DCM is added and the solution is washed withaqueous sodium thiosulfate solution and brine. The organic layer isdried over sodium sulfate. Filtration and evaporation of solvents yieldsthe crude material. Further purification is achieved by chromatography.

The product of the previous step, lithium chloride, triphenylarsine,tributylvinyltin, andtris(dibenzylideneacetone)dipalladium(0)-chloroform adduct are heated inan organic solvent such as N-methylpyrrolidinone at an elevatedtemperature of approximately 55° C., according to a procedure from J.Med. Chem., 1996, 39, 4181-4196. At the end of the reaction, the mixtureis cooled to room temperature and poured into a mixture of ice,potassium fluoride, water, and ethyl acetate. Stirring is continued forone hour. The suspension is filtered through Celite and extracted withethyl acetate. The combined organic extracts are dried over sodiumsulfate. The solvents are removed in vacuo and the crude material isfurther purified by chromatography.

The product of the previous step is dissolved in an organic solvent suchas DCM or THF.1,1,1-tris(acyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martinreagent) is added and the solution is stirred at room temperature,according to a procedure from J. Org. Chem., 1984, 48, 4155-4156. At theend of the reaction diethyl ether is added, followed by aqueous sodiumhydroxide solution. The layers are separated and the organic layer iswashed with aqueous sodium hydroxide solution, water, and dried oversodium sulfate. Filtration and evaporation of solvents yields the crudeproduct. Further purification is achieved by chromatography.

The starting material is dissolved in an organic solvent such astoluene. P(isobutylNCH₂CH₂)₃N, palladium(II) acetate, sodium tert.butoxide, and benzylamine are added and the mixture was heated at 80°C., according to a procedure from J. Org. Chem., 2003, 68, 452-459. Atthe end of the reaction, the mixture is cooled to room temperature andthe solvents are removed in vacuo. The crude material is purified bychromatography. Any residual acetate is removed by brief treatment withmethanolic sodium methoxide.

The benzyl-protected aniline is dissolved in an organic solvent such asDMF. Palladium on carbon is added and the reaction mixture is placedunder an atmosphere of hydrogen. At the end of the reaction, the mixtureis filtered through Celite. The solvents are removed in vacuo. Furtherpurification is achieved by chromatography.

The resulting primary aniline is dissolved in an organic solvent such asTHF, acetonitrile, or DMF and is treated with formaldehyde and sodiumtriacetoxyborohydride as described in J. Org. Chem, 1996, 61, 3849-3862.The reaction is quenched with aqueous sodium bicarbonate and the productis extracted with an organic solvent such as ethyl acetate. The crudematerial is treated with di-t-butyl dicarbonate in an organic solventsuch as dimethylformamide and aqueous sodium hydroxide. The resultingcarbamate is purified by chromatography.

The primary alcohol product is dissolved in an organic solvent such asDCM or THF. 1,1,1-tris(acyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one(Dess-Martin reagent) is added and the solution is stirred at roomtemperature, according to a procedure from J. Org. Chem., 1984, 48,4155-4156. At the end of the reaction diethyl ether is added, followedby aqueous sodium hydroxide solution. The layers are separated and theorganic layer is washed with aqueous sodium hydroxide solution, water,and dried over sodium sulfate. Filtration and evaporation of solventsyields the crude product. Further purification is achieved bychromatography.

The starting material is dissolved in an organic solvent such as DCM orTHF and is treated with the mixed anhydride of formic and pivalic acids,according to a procedure from Recl. Trav. Chem. Pay-Bas, 1982, 101, 460.At the end of the reaction, the solvent and all volatiles are removed invacuo and the crude product is further purified by chromatography.

The product is dissolved in an organic solvent such as DCM or THF.1,1,1-Tris(acyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martinreagent) is added and the solution was stirred at room temperature,according to a procedure from J. Org. Chem., 1984, 48, 4155-4156. At theend of the reaction diethyl ether is added, followed by aqueous sodiumhydroxide solution. The layers are separated and the organic layer iswashed with aqueous sodium hydroxide solution, water, and dried oversodium sulfate. Filtration and evaporation of solvents yields the crudeproduct. Further purification is achieved by chromatography.

R₂ Variants

The starting material is dissolved in an organic solvent such as DMF andreacted with N-chlorosuccinimide, according to a procedure from J. Med.Chem., 1996, 39, 4181-4196. After the starting material is consumed thereaction mixture is poured into water and the product is extracted withdiethyl ether. The combined organic layers are dried over sodiumsulfate. Filtration and evaporation of the solvent yields a crudereaction product.

The product of step one is dissolved in a mixture of organic solventssuch as methanol, DCM, and pyridine. The solution is cooled to −78° C.and ozone is bubbled into the solution until a blue color persists. Theexcess ozone is removed with a nitrogen stream. The reaction mixture iswarmed to room temperature and thiourea is added. Stirring at roomtemperature is continued. The reaction mixture is filtered andpartitioned between DCM and water. The aqueous layer is extracted withDCM and the combined organic layers are washed with HCl (1 N), saturatedaqueous sodium bicarbonate solution and brine. The solution is driedover sodium sulfate. Filtration and evaporation of the solvents yieldsthe crude aldehyde. Further purification is achieved by chromatography.

The starting material is dissolved in a mixture of organic solvents suchas methanol, DCM, and pyridine. The solution is cooled to −78° C. andozone is bubbled into the solution until a blue color persists. Theexcess ozone is removed with a nitrogen stream. The reaction mixture iswarned to room temperature and thiourea is added. Stirring at roomtemperature is continued. The reaction mixture is filtered andpartitioned between DCM and water. The aqueous layer is extracted withDCM and the combined organic layers are washed with HCl (1 N), saturatedaqueous sodium bicarbonate solution, and brine. The solution is driedover sodium sulfate. Filtration and evaporation of the solvents yieldsthe crude aldehyde. Further purification is achieved by chromatography.

The product of step one is dissolved in an organic solvent such asbenzene. Trifluoromethanesulfonyl chloride anddichlorotris(triphenylphosphine)rhuthenium are added and the solution isdegassed. The reaction mixture is heated at 120° C., according to aprocedure from J. Chem. Soc., Perkin Trans. 1, 1994, 1339-1346. At theend of the reaction the mixture is cooled to room temperature and thesolvent is removed in vacuo. Further product purification is achieved bychromatography.

Synthesis of Olefins and Linkers to Phosphonates

The phenacetaldehyde (5.3 g, 15.8 mmol) in toluene (50 mL) was heated at100° C. with 2-(triphenyl-phosphanylidene)-propionaldehyde (6.8 g, 20.5mmol) overnight. After concentration, the residue was purified by silicagel chromatography to provide 4.24 g (72%) of the unsaturated aldehydeas a pale yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H),1.10-1.21 (m, 2H), 1.87 (s, 3H), 2.16 (s, 3H), 3.67-3.76 (m, 2H), 3.74(s, 3H), 4.27-4.39 (m, 2H), 5.11 (s, 2H), 6.40-6.48 (m, 1H), 9.2 (s,1H).

The trimethylsilyethyl protected aldehyde is treated withdiethylphosphite in a solvent such as acetonitrile in the presence of abase such as triethylamine to afford the hydroxy phosphonate, accordingto a procedure such as that reported in Tetrahedron, 1995, 51, 2099. Thehydroxy phosphonate is O-alkylated and then the protecting group isremoved by treatment with either trifluoroacetic acid ortetrabutylammonium fluoride to generate the desired methoxy phosphonateanalog.

Alternatively, the aldehyde is mixed with diethyl(2-aminoethyl)phosphonate and treated with a reducing agent such assodium triacetoxyborohydride to generate the amino phosphonate analog.

A solution of4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal(103 mg, 0.27 mmol) in methanol (5 mL) was cooled to 0° C. A solution ofCeCl₃ (0.68 mL, MeOH: H₂O, 9:1) was added, followed by LiBH₄ (0.14 mL,0.28 mmol of a 2M solution in THF). The ice bath was removed and thereaction mixture was allowed to warm to room temperature. The reactionmixture was stirred for an additional 40 minutes whereupon TLC indicatedcomplete consumption of starting aldehyde. The reaction was worked up byaddition of aqueous 1N HCl (0.5 mL) and the product was extracted withCH₂Cl₂. The organic layer was washed with saturated aqueous sodiumbicarbonate solution and brine. The organic layer was concentrated underreduced pressure and the residue was purified by silica gelchromatography to provide 100 mg (97%) of the product as a clear liquid.¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 9H), 1.20 (dd, 2H, J=7, 8 Hz), 1.81(s, 3H), 2.13 (s, 3H), 3.38-3.50 (m, 2H), 3.74 (s, 3H), 3.95 (s, 2H),4.27 (dd, 2H, J=7, 8 Hz), 5.08 (s, 2H), 5.17-5.44 (m, 1H).

Polymer-supported triphenylphosphine is soaked in DCM for 1 hour. Theallylic alcohol and carbon tetrabromide are sequentially added. When thereaction is complete, the mixture is filtered and the filtrateconcentrated. The bromide is purified as necessary by chromatography.

The allylic bromide is treated in an inert organic solvent such asdimethylformamide with an alkali metal salt of ethyldiethoxyphosphorylacetate (prepared by reacting ethyldiethoxyphosphorylacetate with sodium hexamethyldisilazide or sodiumhydride) to afford the ethoxycarbonyl phosphonate, according to aprocedure such as that described in WO 95/22538. The carboxylic estergroup is converted to both the carboxylic amide and the hydroxymethylgroups according to the methods conventionally utilized for amideformations and ester reductions. For example, the carboxylic ester issaponified with aqueous lithium hydroxide. The acid is activated withethyl chloroformate and reduced with sodium borohydride to generate,after removal of the protecting group, the hydroxymethyl phosphonateanalog. The acid is also converted to its acyl chloride and then reactedwith ethylamine to afford the amide analog.

The aryl acetaldehyde is coupled with 2-(diethoxyphosphoryl)-but-3-enoicacid ethyl ester to generate the 2-vinyl substituted ester, according toa procedure such as that reported in Synthesis, 1999, 282. The 2-vinylgroup is converted to the 2-cyclopropyl group under cyclopropanationconditions such as those described in Tetrahedron Lett. 1998, 39, 8621.The ester is converted to the alcohol, which, optionally, can be furthersubjected to reactions such as that described below to generate variousphosphonate-containing mycophenolic acid analogues.

The allylic alcohol is treated with bromomethylphosphonic aciddiisopropyl ester in the presence of a base such as lithium t-butoxidein a solvent such as dimethylformamide. The phenol protecting group isthen removed by treatment with trifluoroacetic acid.

The phenacetaldehyde can alternatively be converted to the allylphosphonium salt, according to a procedure such as that reported in J.Org. Chem. 1987, 52, 849. The phosphonium salt is then treated with thecommercially available 3,3,3-trifluoro-2-oxo-propionic acid ethyl esterand a base such as sodium hydride to generate the 2-trifluoromethylsubstituted ester. The ester is converted to the alcohol, which,optionally, can be further subjected to reactions described earlier togenerate mycophenolic acid analogues with various side chains containingthe phosphonate group.

Introduction of R₄ Variants

The enone (synthesis reviewed in Tetrahedron, 1985, 41, 4881-4889) andthe diene (Chem. Pharm. Bull., 1989, 37, 2948-2951) are dissolved in anorganic solvent such as toluene, stirred at room temperature for 24hours and heated to reflux for additional 5 hours, according to aprocedure from J. Med. Chem., 1996, 39, 4181-4196. The reaction mixtureis cooled to room temperature and the solvent removed in vacuo. Thecrude reaction product is further purified by chromatography.

The product of step one is dissolved in an organic solvent such as DCMand m-chloroperbenzoic acid is added, according to a procedure from J.Med. Chem., 1996, 39, 4181-4196. At the end of the reaction, thesolution is poured into aqueous sodium hydrogen sulfite solution. Theorganic layer is washed with saturated aqueous sodium bicarbonatesolution and is dried over sodium sulfate. Filtration and evaporation ofsolvents yields the crude product.

The crude product is dissolved in an organic solvent such as toluene andtreated with dichlorodicyanoquinone (DDQ), according to a procedure fromJ. Med. Chem., 1996, 39, 4181-4196. At the end of the reaction thesolvent is removed in vacuo and the crude material is further purifiedby chromatography.

The product is dissolved in an organic solvent such as DCM and treatedwith boron trichloride at reflux temperature, according to a modifiedprocedure from J. Med. Chem., 1996, 39, 46-55. At the end of thereaction the solution is washed with aqueous HCl solution. The solutionis dried over sodium sulfate. Removal of the solvent yields the crudereaction product. Further purification is achieved by chromatography.

The product of the previous step and triphenylphosphine are dissolved inan organic solvent such as tetrahydrofuran (THF).Diisopropylazodicarboxylate (DIAD) is added dropwise at 0° C. Stirringis continued. A solution of 2-trimethylsilyl ethanol in THF is added andstirring is continued. At the end of the reaction, the solvent isremoved in vacuo. The crude reaction solid is extracted with a mixtureof organic solvents such as hexanes and diethylether. The washings arecombined and the solvents removed in vacuo. The desired product isfurther purified and separated from the undesired regioisomer bychromatography.

The starting material is dissolved in an organic solvent such asdimethylformamide (DMF) and reacted with N-chlorosuccinimide, accordingto a procedure from J. Med. Chem., 1996, 39, 4181-4196. After thestarting material is consumed the reaction mixture is poured into waterand the product is extracted with diethyl ether. The combined organiclayers are dried over sodium sulfate. Filtration and evaporation of thesolvents yields the crude product. Further purification is achieved bychromatography.

The starting material is dissolved in an organic solvent such as benzeneand reacted with dimethyl sulfoxide (DMSO), dicyclohexylcarbodiimide(DCC), and orthophosphoric acid according to a procedure from J. Am.Chem. Soc., 1966, 88, 5855-5866. At the end of the reaction, thesuspension is filtered and the organic layer washed with aqueous sodiumbicarbonate solution and dried over sodium sulfate. Filtration andevaporation of solvents yields the crude material. Further purificationis achieved by chromatography.

The product of step one is dissolved in an organic solvent such as DCMor THF and treated with Raney nickel, according to procedures reviewedin Chem. Rev., 1962, 62, 347-404. When all starting material isconsumed, the reaction is filtered and the solvent removed in vacuo.Further purification is achieved by chromatography.

The starting material is dissolved in an organic solvent such as DCM andbromine is added, according to a procedure from J. Med. Chem., 1996, 39,4181-4196. At the end of the reaction, additional DCM is added and thesolution washed with aqueous sodium thiosulfate solution and brine. Theorganic layer is dried over sodium sulfate. Filtration and evaporationof solvents yields the crude material. Further purification is achievedby chromatography on silica gel.

The starting material, lithium chloride, triphenylarsine,tributylvinyltin, andtris(dibenzylideneacetone)dipalladium(0)-chloroform adduct are heated inan organic solvent such as N-methylpyrrolidinone at an elevatedtemperature of approximately 55° C., according to a procedure from J.Med. Chem., 1996, 39, 4181-4196. At the end of the reaction, the mixtureis cooled to room temperature and poured into a mixture of ice,potassium fluoride, water, and ethyl acetate. Stirring is continued for1 hour. The suspension is filtered through Celite and extracted withethyl acetate. The combined organic extracts are dried over sodiumsulfate. The solvents are removed in vacuo and the crude material isfurther purified by chromatography.

The product of step two is dissolved in a mixture of organic solventssuch as benzene and ethyl acetate. Tris(triphenylphosphine)rhodium(I)chloride is added and the reaction is placed under an atmosphere ofhydrogen, according to a procedure from J. Med. Chem., 1996, 39,4181-4196. The solvents are removed in vacuo and the crude reaction isfiltered through silica gel. Further purification is achieved bychromatography.

The starting material is dissolved in an organic solvent such as DMF.Potassium carbonate and allyl bromide are added and stirring at roomtemperature is continued, according to a procedure from J. Med. Chem.,1996, 39, 4181-4196. After all the starting material is consumed,aqueous HCl solution and diethyl ether are added and the organic layeris collected and the solvent is removed in vacuo.

The crude material is dissolved in N,N diethylaniline and the reactionmixture is heated at an elevated temperature of ca. 180° C. At the endof the reaction, the mixture is cooled to room temperature and pouredinto a mixture of aqueous HCl (2N) and ethyl acetate. The organic layeris washed with aqueous HCl (2N) and dried over sodium sulfate.Filtration and removal of the solvents yields the crude product. Furtherpurification is achieved by chromatography.

The product of step 2 is dissolved in a mixture of organic solvents suchas methanol, DCM, and pyridine. The solution is cooled to −78° C. andozone is bubbled into the solution until a blue color persists. Theexcess ozone is removed with a nitrogen stream. The reaction mixture iswarmed to room temperature and thiourea is added. Stirring at roomtemperature is continued. The reaction mixture is filtered andpartitioned between DCM and water. The aqueous layer is extracted withDCM and the combined organic layers are washed with HCl (1 N), saturatedaqueous sodium bicarbonate solution and brine. The solution is driedover sodium sulfate. Filtration and evaporation of the solvents yieldsthe crude aldehyde. Further purification is achieved by chromatography.

The aldehyde is dissolved in an organic solvent such as THF and isreacted with triphenylphosphonium sec.propyl bromide and potassiumtert.butoxide, according to procedures reviewed in Chem. Rev., 1989, 89,863-927. At the end of the reaction, the solvent is removed in vacuo andthe crude material purified by chromatography.

(A) Introduction of Linkers to Phosphonates

The phenols shown herein may optionally be alkylated with the reagent ofchoice. Optionally, the phosphonate moiety will be part of such areagent. Alternatively, it will be introduced in a subsequent step by avariety of means, of which three are illustrated above. For example, analkyl halide may be heated with triethylphosphite in a solvent such astoluene (or other Arbuzov reaction conditions: see Engel, R., “Synthesisof Carbon-phosphorus Bonds,” CRC press, 1988). Alternatively, an epoxidemay be reacted with the anion of a dialkyl phosphinate. In a furtherexample, the phosphonate reagent may be the electrophile, e.g., anacetylide anion may be condensed with phosphorus oxychloride and theintermediate dichlorophosphonate quenched with ethanol to generate thediethyl ester of the desired phosphonic acid.

Example 333

A specific compound of the invention can be prepared as follows.

[4-(6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonicacid

This product was prepared using methods similar to those describedherein, e.g., in Examples 292 and 317. MS (negative mode): 369.3 [M⁺−1].

Example 333A

A specific compound of the invention can be prepared as follows.

2-{[4-(6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phenoxy-phosphinoylamino}-propionicacid ethyl ester

Using methods similar to those described herein, e.g., in Example 302,the desired product was prepared, starting from Example 333. MS(positive mode): 546.3 [M⁺+1] & 568.3 [M⁺+Na].

Example 334

A specific compound of the invention can be prepared as follows:

2-({2-[4-(6-Ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl}-phenoxy-phosphinoylamino)-propionicacid ethyl ester

This product was prepared using methods analogous to those describedherein, e.g., in Examples 309 and 333, using2-[(2-amino-ethyl)-phenoxy-phosphinoylamino]-propionic acid ethyl esterin the reductive amination step. MS (positive mode): 559.4 [M⁺+1] &581.3 [M⁺+Na].

Example 335

A specific compound of the invention can be prepared as follows:

2-((1-Ethoxycarbonyl-ethylamino)-{2-[4-(6-ethyl-4-hydroxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enylamino]-ethyl}-phosphinoylamino)-propionicacid ethyl ester

This product was prepared by methods analogous to those describedherein, e.g., in Example 334, using2-[(2-aminoethyl)-(1-ethoxycarbonyl-ethylamino)-phosphinoylamino]-propionicacid ethyl ester in the reductive amination step. MS (positive mode):582.4 [M⁺+1] & 604.3 [M⁺+Na].

Example 336(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-methyl)-phosphonicacid diethyl ester

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (67.0 mg, 177 μmol) in DMF (3.0 mL) wasadded diethyl cyanophosphonate (34.8 μL, 230 μmol) anddiisopropylethylamine (Hunig's Base, DIEA, 30.4 μL, 177 μmol). Thesolution was stirred at ambient temperature for 4 hours whendiethyl(aminomethyl)-phosphonate (45.4 mg, 177 μmol) was added. Thesolution was stirred for 4 additional hours, when complete consumptionof the starting materials was observed. The reaction was worked up byremoval of the solvent in vacuo and purifying the residue by silica gelchromatography using MeOH—CH₂Cl₂ (10-30%). The product collected fromthis chromatography step was sufficiently pure to be carried on to thenext reaction. A small amount of the product (20 mg) was repurified byRP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) to provide 12.9 mg(76%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.19 (t, 6H,J=7.2 Hz), 3.21 (s, 3H), 3.70 (m, 2H), 4.00 (q, 4H, J=7.2 Hz), 4.81 (s,2H), 6.81 (d, 2H, J=9 Hz), 7.71 (d, 2H, J=9 Hz), 8.40 (br s, 1H), 8.61(s, 1H). ³¹P (121.4 MHz, DMSO-d₆) δ 23.4. MS (m/z) 475.2 [M+H]⁺, 597.2[M+Na]⁺.

Example 337(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-methyl)-phosphonicacid

To a solution of crude(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonicacid diethyl ester post silica column chromatography (60 mg, 126 μmol)in dry DMF (0.90 mL) was added trimethylsilyl bromide(bromotrimethylsilane, TMSBr, 130.6 μL, 1,010 μmol) at ambienttemperature. The solution was then heated at 70° C. for 4.0 hours, afterwhich the reaction mixture was allowed to cool to room temperature. Thesolvent volume was reduced to ˜700 μL in vacuo and diluted with H₂O (100μL). This solution was purified by RP HPLC on C₁₈ column usingH₂O/acetonitrile (2-95%) to provide 26.8 mg (51%) of the desiredcompound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 3.18 (s, 3H),3.50 (m, 2H), 4.77 (s, 2H), 6.79 (d, 2H, J=9 Hz), 7.79 (d, 2H, J=9 Hz),8.07 (br s, 1H), 8.56 (s, 1H); MS (m/z) 419.2 [M+H]⁺.

Example 338(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonicacid diethyl ester

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (61.2 mg, 161 μmol) in DMF (2.8 mL) wereadded diethyl cyanophosphonate (31.8 μL, 210 μmol) and DIEA (27.8 μL,161 μmol). The solution was stirred at ambient temperature for 4 hours,when diethyl(aminoethyl)phosphonate (43.8 mg, 161 μmol) was added. Thesolution was stirred for 3 additional hours, by which time completeconsumption of the starting materials was observed. The reaction wasworked up by removal of the solvent in vacuo and purifying the residueby silica gel chromatography using MeOH—CH₂Cl₂ (10-30%). The productcollected from this chromatography step was sufficiently pure to becarried on to the next reaction. A small amount of the product (32 mg)was re-purified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%)to provide 19 mg (70%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ1.21 (t, 6H, J=7 Hz), 1.95-2.05 (m, 2H), 3.20 (s, 3H), 3.13-3.22 (m,2H), 3.98 (appt septet, 4H, J=7 Hz), 4.79 (s, 2H), 6.80 (d, 2H, J=9 Hz),7.65 (d, 2H, J=9 Hz), 8.20 (br s, 1H), 8.60 (s, 1H). ³¹P (121.4 MHz,DMSO-d₆) δ 28.9. MS (m/z) 489.2 [M+H]⁺, 511.2 [M+Na]⁺.

Example 339(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonicacid

To a solution of crude(2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonicacid diethyl ester post silica column chromatography (61 mg, 125 μmol)in dry DMF (1.00 mL) was added TMSBr (129.0 μL, 999.2 μmol) at ambienttemperature. The solution was then heated at 70° C. for 5.5 hours, whenLCMS analysis demonstrated the reaction to be 90% complete. The reactionmixture was allowed to cool to room temperature and stirred for anadditional 12 hours. The reaction was worked up by removal of thesolvent in vacuo and dissolving the residue in DMF/H₂O (800 μL, 1:1) and1N aqueous NaOH (15 μL). The product was purified by RP HPLC on C₁₈column using H₂O/acetonitrile (2-95%) to provide 29 mg (53%) of thedesired compound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ1.67-1.85 (m, 2H), 3.19 (s, 3H), 3.25-3.40 (m, 2H), 4.76 (s, 2H), 6.71(br s, 2H), 5.80 (d, 2H, J=9 Hz), 7.64 (d, 2H, J=9 Hz), 7.73 (br s, 2H),8.15 (br s, 1H), 8.56 (s, 1H). ³¹P (121.4 MHz, DMSO-d₆) δ 23.0. MS (m/z)431.3 [M−H]⁻.

Example 340(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-phosphonicacid diethyl ester

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (61.2 mg, 161 μmol) in DMF (2.8 mL) wereadded diethyl cyanophosphonate (31.8 μL, 210 μmol) and DIEA (27.8 μL,161 μmol). The solution was stirred at ambient temperature for 3 hours,when diethyl(aminopropyl)phosphonate (34.9 mg, 122.6 μmol) was added.The solution was stirred for 2 additional hours, whereupon completeconsumption of the starting materials was observed. The reaction wasworked up by removal of the solvent in vacuo and purifying the residueby silica gel chromatography using MeOH—CH₂Cl₂ (10-30%). The product(65.5 mg) collected from this chromatography step was sufficiently pureto be carried on to the next reaction. A small amount (32.8 mg) wasre-purified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 23.2 mg (75%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ1.20 (t, 6H, J=7.2 Hz), 1.64-1.75 (m, 4H), 3.22 (s, 3H), 3.41 (m, 2H),3.98 (appt septet, 4H, J=7.2 Hz), 4.85 (s, 2H), 6.79 (d, 2H, J=9 Hz),7.68 (d, 2H, J=9 Hz), 8.17 (br s, 1H), 8.70 (s, 1H); ³¹P (121.4 MHz,DMSO-d₆) δ 31.9; MS (m/z) 503.2 [M+H]⁺.

Example 341(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-phosphonicacid

To a solution of crude(2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-phosphonicacid diethyl ester post silica column chromatography (32.2 mg, 66.2μmol) in dry DMF (0.50 mL) was added TMSBr (68.0 μL, 529.6 μmol) atambient temperature. The solution was then heated at 70° C. for 1.0hour, when LCMS analysis demonstrated the reaction to be complete. Thereaction mixture was allowed to cool to room temperature, and water (60μL) and methanol (60 μL) were added. The crude reaction mixture waspurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 11.2 mg (38%) of the desired compound as a yellow solid. ¹H NMR(300 MHz, DMSO-d₆) δ 1.50 (m, 2H), 1.61 (m, 2H), 3.22 (s, 3H), 3.25-3.40(m, 2H), 4.84 (s, 2H), 6.80 (d, 2H, J=9 Hz), 7.69 (d, 2H, J=9 Hz), 8.20(br s, 1H), 8.69 (s, 1H). ³¹P (121.4 MHz, DMSO-d₆) δ 26.3. MS (m/z)447.3 [M−H]⁻.

Example 3422-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methyl-amino]benzoylamino}-ethyl)phenoxyphosphinoyloxy]propionicacid ethyl ester [diastereomeric mixture at phosphorus]

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (60.0 mg, 158.3 μmol) in DMF (2.5 mL) wereadded diethyl cyanophosphonate (31.2 μL, 205.7 μmol) and DIEA (81.8 μL,474.9 μmol). The solution was stirred at ambient temperature for 3.5hours, when a solution of(S)-2-[(2-aminoethyl)phenoxyphosphinoyloxy]-propionic acid ethyl estermono acetic acid salt (57.1 mg, 158.3 μmol; mixture of diastereomers atphosphorus) in DMF (200 μL) was added. The solution was stirred for 1.5additional hours, whereupon complete consumption of the startingmaterials was observed. The solvent was removed in vacuo and the crudematerial was purified by silica gel chromatography using MeOH—CH₂Cl₂(10-30%). A small amount of the product (24.8 mg) was repurified by RPHPLC on C₁₈ column using H₂O/acetonitrile (2-95%) to provide 15.8 mg(65%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.17-1.27 (m,3H), 1.32 (d, 2H, J=7.5 Hz), 1.42 (d, 1H, J=7.5 Hz) 2.27 (m, 2H), 3.19(s, 3H), 3.53 (m, 2H), 4.08-4.14 (m, 2H), 4.77 (s, 2H), 4.98 (m, 1H),6.72 (br s, 1H), 6.81 (d, 2H, J=9 Hz), 7.21 (m, 3H), 7.36 (m, 2H), 7.66(d, 2H, J=9 Hz), 8.26 (br s, 1H), 8.56 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆)δ 26.6, 27.4. MS (m/z) 609.2 [M+H]⁺.

Example 3432-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methyl-amino]benzoylamino}-ethyl)phenoxyphosphinoyloxy]-propionicacid [diastereomeric mixture at phosphorus]

To a solution of2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methyl-amino]benzoylamino}ethyl)phenoxy-phosphinoyloxy]propionicacid ethyl ester (mixture of diastereomers at phosphorus; 40.0 mg, 65.7μmol) in DMF (0.4 mL), acetonitrile (0.2 mL) and water (0.2 mL) wasadded aqueous sodium hydroxide (1 N, 131.4 μL). The solution was stirredat ambient temperature for 4 hours. The solvents were removed in vacuoand the crude product was purified by RP HPLC on C₁₈ column usingH₂O/acetonitrile (2-95%) to provide 23.7 mg (71.3%) of the pure product.¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (d, 2H, J=6.9 Hz), 1.79 (m, 2H), 3.21(s, 3H), 3.37 (m, 2H), 4.61 (m, 1H), 4.81 (s, 2H), 6.79 (d, 2H, J=8.7Hz), 7.64 (d, 2H, J=9.7 Hz), 8.25 (br s, 1H), 8.63 (s, 1H); ³¹P (121.4MHz, DMSO-d₆) δ 25.1. MS (m/z) 505.2 [M+H]⁺.

Example 343A2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]-benzoy-lamino}ethyl)phenoxyphosphinoyloxy]propionicacid ethyl ester [diastereomerically pure at phosphorus]

To a solution of4-[(2,4-diaminopteridin-6-ylmethyl)-methyl-amino]benzoic acidhemihydrochloride dihydrate (101.9 mg, 268.9 μmol) in DMF (3.3 mL) wereadded diethyl cyanophosphonate (53.0 μL, 349.5 μmol) and DIEA (138.0 μL,806.7 μmol). The solution was stirred at ambient temperature for 2.5hours, whereupon (S)-2-[(2-aminoethyl)phenoxyphosphinoyloxy]-propionicacid ethyl ester mono acetic acid salt (diastereomerically pure atphosphorus; 268.9 μmol) in DMF (500 μL) was added. The solution wasstirred for 30 additional minutes, whereupon complete consumption of thestarting materials was observed. The solvent was removed in vacuo andthe crude material was purified by silica gel chromatography usingMeOH—CH₂Cl₂ (10-30%). A small amount of the product (40.0 mg) wasrepurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 28.7 mg (75.1%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ1.15 (t, 3H, J=7.2 Hz), 1.44 (d, 3H, J=6.9 Hz), 2.26 (m, 2H), 3.23 (s,3H), 3.51 (m, 2H), 4.09 (q, 2H, J=7.2 Hz), 4.86 (s, 2H), 5.01 (m, 1H),6.81 (d, 2H, J=9.3 Hz), 7.21 (m, 3H), 7.35 (m, 2H), 7.68 (d, 2H, J=9.3Hz), 8.29 (br s, 1H), 8.71 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 26.6. MS(m/z) 609.2 [M+H]⁺.

Example 3442-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]-benzoylamino}-ethyl)-phenoxyphosphinoylamino]propionicacid ethyl ester (mixture of diastereomers at phosphorus)

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (39.6 mg, 104.0 μmol) in DMF (1.2 mL) wereadded diethyl cyanophosphonate (20.6 μL, 136.1 μmol) and DIEA (36.0 μL,209.4 μmol). The solution was stirred at ambient temperature for 3hours, when (S)-2-[(2-aminoethyl)phenoxyphosphinoylamino]propionic acidethyl ester mono acetic acid salt (mixture of diastereomers atphosphorus; 104.0 μmol) in DMF (200 μL) was added. The solution wasstirred for 30 minutes when complete consumption of the startingmaterials was observed. An aliquot (66%) of the reaction was purified bysilica gel chromatography using MeOH—CH₂Cl₂ (10-30%), yielding 27.2 mgof crude product. A small amount of the product (10 mg) was repurifiedby RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) to provide 4.2mg (26%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.11 (t, 3H,J=6.9 Hz), 1.18 (d, 3H, J=7.2 Hz), 2.06-2.17 (m, 2H), 3.20 (s, 3H), 3.51(m, 2H), 3.88 (m, 1H), 4.02 (m, 2H), 4.79 (s, 2H), 5.61 (m, 1H), 6.80(d, 2H, J=9 Hz), 6.98 (br s, 1H), 7.18 (m, 3H), 7.32 (m, 2H), 7.67 (d,2H, J=9 Hz), 8.20 (br s, 1H), 8.59 (s, 1H) ³¹P (121.4 MHz, DMSO-d₆) δ29.5, 30.1. MS (m/z) 608.2 [M+H]⁺.

Example 3452-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6-(diethoxy-phosphoryl)-hexanoicacid

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (63.0 mg, 166.2 μmol) in DMF (2.8 mL) wereadded diethyl cyano phosphonate (30.8 μL, 199.4 μmol) and DIEA (85.8 μL,498.6 μmol). The solution was stirred at ambient temperature for 3.5hours when (L)-2-amino-6-diethylphosphonatohexanoic acid (44.3 mg, 166.2μmol) was added. The solution was stirred for 48 additional hours. Thereaction was worked up by removal of the solvent in vacuo and purifyingthe residue by silica gel chromatography using MeOH—CH₂Cl₂ (10-30%). Theproduct (87 mg) collected from this chromatography step was sufficientlypure to be carried on to the next reaction. An aliquot of the product(51.0 mg) was repurified by RP HPLC on C₁₈ column using H₂O/acetonitrile(2-95%) to provide 24.7 mg (44%) of the pure product. ¹H NMR (300 MHz,DMSO-d₆) δ 1.18 (t, 6H, J=6.9 Hz), 1.42 (m, 4H), 1.65 (m, 4H), 3.20 (s,3H), 3.92 (m, 4H), 4.29 (m, 1H), 4.78 (s, 2H), 6.72 (br s, 1H), 6.81 (d,2H, J=9 Hz), 7.73 (d, 2H, J=9 Hz), 8.14 (d, 1H, J=7.8 Hz), 8.56 (s, 1H);³¹P (121.4 MHz, DMSO-d₆) δ 31.8; MS (m/z) 574.3 [M]⁺.

Example 3462-{4-[(2,4-Diaminopteridin-6-ylmethyl)methylamino]-benzoylamino}-6-(phosphoryl)hexanoicacid

To a solution of crude(2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino})-2′(L)-(6′-(phosphonic acid diethyl ester) hexanoic acid) post silicacolumn chromatography (20 mg, 34.6 μmol) in dry DMF (0.60 mL) was addedTMSBr (18.0 μL, 139.2 mmol) at ambient temperature. The solution wasthen heated at 70° C. for 18 hours, after which the reaction mixture wasallowed to cool to room temperature. The solvent was removed in vacuoand dissolved in DMF (400 μL) and water (60 μL). This solution waspurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 8.9 mg (49%) of the product as a yellow solid. ¹H NMR (300 MHz,DMSO-d₆) δ 1.45 (m, 6H), 1.75 (m, 2H), 3.20 (s, 3H), 4.25 (m, 1H), 4.77(s, 2H), 6.62 (br s, 1H), 6.80 (d, 2H, J=8.7 Hz), 7.73 (d, 2H, J=8.7Hz), 8.14 (br s, 1H), 8.55 (s, 1H); MS (m/z) 519.2 [M+H]⁺.

Example 3472-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl-phosphonate)hexanoic acid

The ethyl-TMS ester is hydrolyzed under suitable conditions to providethe corresponding acid of the invention.

The intermediate2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl-phosphonate)-hexanoic acid TMS ethanol ester can be prepared asfollows.

a. (L)-2-Cbz-Amino-hexanoic acid 6-phosphonic acid

To a suspension of (L)-2-amino-6-(diethoxyphosphonyl)hexanoic acid (106mg, 396.8 μmol) in dry DMF (2.00 mL) was added TMSBr (307.0 μL, 2,381.0μmol) at ambient temperature. The solution was then heated at 70° C. for2 hours, after which the reaction mixture was allowed to cool to roomtemperature. The solvent was removed in vacuo. The crude material wasdissolved in water (0.25 mL) and NaOH (1-N, 2.50 mL). Benzylchloroformate (79.3 μL, 555.5 μmol) was added and stirring at roomtemperature was continued. After 2 hours, the solution was washed withether (2 mL) and the aqueous layer was acidified with aqueous HCl topH 1. The aqueous layer was extracted with EtOAc (3×5 mL). The combinedorganic extracts were dried over sodium sulfate. Filtration andevaporation of solvents yielded a crude product, which was sufficientlypure for further transformations. ¹H NMR (300 MHz, DMSO-d₆) δ 1.42-1.65(m, 8H), 3.90 (m, 1H), 5.02 (s, 2H), 7.32 (s, 5H), 7.55 (m, 1H), 7.94(s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 26.5; MS (m/z) 345.6 [M+H]⁺.

b. (L)-2-Amino-hexanoic acid 2′ TMS ethyl ester-6-phosphonic acid monophenyl ester

To a solution of (L)-2-Cbz-amino-hexanoic acid-6-phosphonic acid (137.3mg, 397.9 μmol) in 2-TMS ethanol (2.5 mL) was added acetyl chloride (50μL). Stirring at room temperature was continued. After 22 hours completeconversion was observed. The solvents were removed in vacuo. The crudematerial was sufficiently pure for the next step.

One half of the crude material (198.9 μmol) was dissolved in toluene(3.0 mL) at room temperature. Thionyl chloride (167.2 mg, 1,416.0 μmol)was added and the reaction mixture was heated at 70° C. (oil bath).After 4 hours, the reaction was cooled to room temperature and thesolvent was removed in vacuo. The crude material was re-dissolved inmethylene chloride (2.0 mL) and a solution of phenol (36.6 mg, 389.0μmol) and DIEA (67.0 μL, 389.0 μmol) in methylene chloride (1.0 mL) wasadded. Stirring at room temperature was continued. After 4 hrs thesolvents were removed in vacuo.

The crude material was dissolved in tetrahydrofuran (THF) (3.0 mL) andaqueous sodium hydroxide solution (1N, 0.885 mL) was added. Stirring atroom temperature was continued. After 14 hours the solvent was removedin vacuo to provide the crude phosphonate mono phenyl ester (63.8 mg).This material was dissolved in 2-TMS ethanol (1.0 mL) and acetylchloride (20 μL) was added. Stirring at room temperature was continued.After 22 hours complete conversion to the carboxylate ester wasobserved. The solvents were removed in vacuo. The material wassufficiently pure for the next step.

One half of the crude material (75 μmol) was dissolved in ethanol (1.5mL). Pd/C (5%, 20 mg) was added and the reaction was placed under anatmosphere of hydrogen gas. After 1.5 hours Celite was added and thecrude reaction mixture was filtered through Celite. The solvents wereremoved in vacuo and the crude material was used in the next stepwithout further purification.

c.2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl-phosphonate)-hexanoic acid TMS ethanol ester

To a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (22.7 mg, 60.0 μmol) in DMF (0.80 mL) wereadded diethyl cyano phosphonate (12.4 μL, 78.0 μmol) and DIEA (31.0 μL,180.0 μmol). The solution was stirred at ambient temperature for onehour when (L)-2-amino-6-monophenoxyphosphonatohexanoic acid 2′ TMS ethylester (70.5 μmol), suspended in DMF (0.2 mL), was added. The solutionwas stirred for 3.5 additional hours. The crude reaction mixture waspurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (5-95%) toprovide 19.4 mg (46%) of2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl-phosphonate)-hexanoic acid TMS ethanol ester. ¹H NMR (300 MHz,DMSO-d₆) δ 0.0 (s, 9H), 0.91 (t, 2H, J=8.1 Hz), 1.42-1.53 (m, 4H),1.67-1.76 (m, 4H), 3.24 (s, 3H), 4.10 (t, 2H, J=8.1 Hz), 4.29 (m, 1H),4.86 (s, 2H), 6.81 (d, 2H, J=9 Hz), 7.12 (m, 3H), 7.31 (m, 2H), 7.74 (d,2H, J=9 Hz), 8.14 (d, 1H, J=7.8 Hz), 8.71 (s, 1H); ³¹P (121.4 MHz,DMSO-d₆) δ 26.2; MS (m/z) 695.2 [M]⁺.

Example 347A4-[(2,4-Diamino-pteridin-6-ylmethyl)methylamino]-benzoylamino}-6′-(monophenyl mono (S) ethyl lactate-phosphonate)hexanoic acid

The ethyl-TMS ester is hydrolyzed under suitable conditions to providethe corresponding acid of the invention.

The intermediate2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl mono (S) ethyl lactate-phosphonate)-hexanoic acid TMS ethanolester can be prepared as follows.

a.2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl mono (S) ethyl lactate-phosphonate)-hexanoic acid TMS ethanolester

To a solution of2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl-phosphonate)-hexanoic acid TMS ethanol ester (14.5 mg, 20.8 μmol,Example 225) in DMF (0.70 mL) was added PYBOP (32.4 mg, 62.4 μmol), DIEA(21.4 mg, 166.4 μmol) and (S) ethyl lactate (19.6 mg, 166.4 μmol). Thereaction mixture was stirred at room temperature for one hour. The crudereaction mixture was purified by RP HPLC on C₁₈ column usingH₂O/acetonitrile (5-95%) to provide 13.5 mg (81%) of the pure product asa mixture of diastereomers at phosphorus (˜4:1). ¹H NMR (300 MHz, CDCl₃)δ 0.0 (s, 9H), 1.02 (t, 2H, J=8.7 Hz), 1.23 (t, 3H, J=9.3 Hz), 1.35 (d,2.4H, J=6.6 Hz), 1.42-1.53 (m, 4.6H), 1.67-1.86 (m, 4H), 3.14 (s, 3H),4.03-4.27 (m, 4H), 4.71 (br s, 3H), 4.98 (m, 0.8H), 5.10 (m, 0.2H), 6.57(d, 2H, J=7.5 Hz), 7.00 (m, 1H), 7.16 (m, 3H), 7.30 (m, 2H), 7.63 (d,2H, J=7.5 Hz), 8.43 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 30.5, 29.2; MS(m/z) 795.2 [M]⁺.

Example 348

By way of example and not limitation, embodiments of the invention arenamed below in tabular format (Table 100). These embodiments are of thegeneral formula “MBF”:

Each embodiment of MBF is depicted as a substituted nucleus (Sc). Sc isdescribed in formula 1-151 herein, wherein A⁰ is the point of covalentattachment of Sc to Lg, as well as in Tables 1.1 to 1.5 below. For thoseembodiments described in Table 100, Sc is a nucleus designated by anumber and each substituent is designated in order by letter or number.Tables 1.1 to 1.5 are a schedule of nuclei used in forming theembodiments of Table 100. Each nucleus (Sc) is given a numberdesignation from Tables 1.1 to 1.5, and this designation appears firstin each embodiment name. Similarly, Tables 10.1 to 10.19 and 20.1 to20.36 list the selected linking groups (Lg) and prodrug (Pd¹ and Pd²)substituents, again by letter or number designation, respectively.Accordingly, a compound of the formula MBF includes compounds having Scgroups based on formula 1-151 herein as well as compounds according toTable 100 below. In all cases, compounds of the formula MBF have groupsLg, Pd¹ and Pd² setforth in the Tables below.

Accordingly, each named embodiment of Table 100 is depicted by a numberdesignating the nucleus from Table 1.1-1.5, followed by a letterdesignating the linking group (Lg) from Table 10.1-10.19, and twonumbers designating the two prodrug groups (Pd¹ and Pd²) from Table20.1-20.36. In graphical tabular form, each embodiment of Table 100appears as a name having the syntax:

Sc.Lg.Pd¹.Pd²

Each Sc group is shown having a tilda (“˜”). The tilda is the point ofcovalent attachment of Sc to Lg. Q¹ and Q² of the linking groups (Lg),it should be understood, do not represent groups or atoms but are simplyconnectivity designations. Q¹ is the site of the covalent bond to thenucleus (Sc) and Q² is the site of the covalent bond to the phosphorousatom of formula MBF. Each prodrug group (Pd¹ and Pd²) are covalentlybonded to the phosphorous atom of MBF at the tilda symbol (“˜”). Someembodiments of Tables 10.1-10.19 and 20.1-20.36 may be designated as acombination of letters and numbers (Table 10.1-10.19) or number andletter (Table 20.1-20.36). For example there are Table 10 entries forBJ1 and BJ2. In any event, entries of Table 10.1-10.19 always begin witha letter and those of Table 20.1-20.36 always begin with a number. Whena nucleus (Sc) is shown enclosed within square brackets (“[ ]”) and acovalent bond extends outside the brackets, the point of covalentattachment of Sc to Lg may be at any substitutable site on SC. Selectionof the point of attachment is described herein. By way of example andnot limitation, the point of attachment is selected from those depictedin the schemes and examples.

TABLE 1.1

TABLE 1.2

TABLE 1.3

TABLE 1.4

TABLE 1.5

TABLE 10.1

Q¹—Q² B

TABLE 10.2

TABLE 10.3

TABLE 10.4

TABLE 10.5

TABLE 10.6

Table 10.7

TABLE 10.7

BQ

BR

BS

BT

BU

BV

TABLE 10.8

TABLE 10.9

TABLE 10.10

TABLE 10.11

TABLE 10.12

TABLE 10.13

TABLE 10.14

TABLE 10.15

TABLE 10.16

TABLE 10.17

TABLE 10.18

TABLE 10.19

TABLE 20.1

TABLE 20.2

TABLE 20.3

TABLE 20.4

TABLE 20.5

TABLE 20.6

TABLE 20.7

TABLE 20.8

TABLE 20.9

TABLE 20.10

TABLE 20.11

TABLE 20.12

TABLE 20.13

TABLE 20.14

TABLE 20.15

TABLE 20.16

TABLE 20.17

TABLE 20.18

TABLE 20.19

TABLE 20.20

TABLE 20.21

TABLE 20.22

TABLE 20.23

132

133

134

135

136

137

138

139

TABLE 20.24

140

141

142

143

144

145

146

147

TABLE 20.25

148

149

150

151

152

153

154

155

156

157

158

159

TABLE 20.26

160

161

162

163

164

165

166

167

168

169

170

171

TABLE 20.27

172

173

174

175

176

177

178

179

TABLE 20.28

180

181

182

183

184

185

TABLE 20.29

186

187

188

189

190

191

192

193

TABLE 20.30

194

195

196

197

198

199

TABLE 20.31

200

201

202

203

204

205

206

207

TABLE 20.32

208

209

210

211

212

213

TABLE 20.33

214

215

216

217

218

219

220

221

TABLE 20.34

222

223

224

225

226

227

TABLE 20.35

228

229

230

231

232

233

234

235

TABLE 20.36

236

237

238

239

240

241

242

243

TABLE 20.37

244

245

246

247

TABLE 100 Prodrugs of 1.B 1.B.228.228; 1.B.228.229; 1.B.228.230;1.B.228.231; 1.B.228.236; 1.B.228.237; 1.B.228.238; 1.B.228.239;1.B.228.154; 1.B.228.157; 1.B.228.166; 1.B.228.169; 1.B.228.172;1.B.228.175; 1.B.228.240; 1.B.228.244; 1.B.229.228; 1.B.229.229;1.B.229.230; 1.B.229.231; 1.B.229.236; 1.B.229.237; 1.B.229.238;1.B.229.239; 1.B.229.154; 1.B.229.157; 1.B.229.166; 1.B.229.169;1.B.229.172; 1.B.229.175; 1.B.229.240; 1.B.229.244; 1.B.230.228;1.B.230.229; 1.B.230.230; 1.B.230.231; 1.B.230.236; 1.B.230.237;1.B.230.238; 1.B.230.239; 1.B.230.154; 1.B.230.157; 1.B.230.166;1.B.230.169; 1.B.230.172; 1.B.230.175; 1.B.230.240; 1.B.230.244;1.B.231.228; 1.B.231.229; 1.B.231.230; 1.B.231.231; 1.B.231.236;1.B.231.237; 1.B.231.238; 1.B.231.239; 1.B.231.154; 1.B.231.157;1.B.231.166; 1.B.231.169; 1.B.231.172; 1.B.231.175; 1.B.231.240;1.B.231.244; 1.B.236.228; 1.B.236.229; 1.B.236.230; 1.B.236.231;1.B.236.236; 1.B.236.237; 1.B.236.238; 1.B.236.239; 1.B.236.154;1.B.236.157; 1.B.236.166; 1.B.236.169; 1.B.236.172; 1.B.236.175;1.B.236.240; 1.B.236.244; 1.B.237.228; 1.B.237.229; 1.B.237.230;1.B.237.231; 1.B.237.236; 1.B.237.237; 1.B.237.238; 1.B.237.239;1.B.237.154; 1.B.237.157; 1.B.237.166; 1.B.237.169; 1.B.237.172;1.B.237.175; 1.B.237.240; 1.B.237.244; 1.B.238.228; 1.B.238.229;1.B.238.230; 1.B.238.231; 1.B.238.236; 1.B.238.237; 1.B.238.238;1.B.238.239; 1.B.238.154; 1.B.238.157; 1.B.238.166; 1.B.238.169;1.B.238.172; 1.B.238.175; 1.B.238.240; 1.B.238.244; 1.B.239.228;1.B.239.229; 1.B.239.230; 1.B.239.231; 1.B.239.236; 1.B.239.237;1.B.239.238; 1.B.239.239; 1.B.239.154; 1.B.239.157; 1.B.239.166;1.B.239.169; 1.B.239.172; 1.B.239.175; 1.B.239.240; 1.B.239.244;1.B.154.228; 1.B.154.229; 1.B.154.230; 1.B.154.231; 1.B.154.236;1.B.154.237; 1.B.154.238; 1.B.154.239; 1.B.154.154; 1.B.154.157;1.B.154.166; 1.B.154.169; 1.B.154.172; 1.B.154.175; 1.B.154.240;1.B.154.244; 1.B.157.228; 1.B.157.229; 1.B.157.230; 1.B.157.231;1.B.157.236; 1.B.157.237; 1.B.157.238; 1.B.157.239; 1.B.157.154;1.B.157.157; 1.B.157.166; 1.B.157.169; 1.B.157.172; 1.B.157.175;1.B.157.240; 1.B.157.244; 1.B.166.228; 1.B.166.229; 1.B.166.230;1.B.166.231; 1.B.166.236; 1.B.166.237; 1.B.166.238; 1.B.166.239;1.B.166.154; 1.B.166.157; 1.B.166.166; 1.B.166.169; 1.B.166.172;1.B.166.175; 1.B.166.240; 1.B.166.244; 1.B.169.228; 1.B.169.229;1.B.169.230; 1.B.169.231; 1.B.169.236; 1.B.169.237; 1.B.169.238;1.B.169.239; 1.B.169.154; 1.B.169.157; 1.B.169.166; 1.B.169.169;1.B.169.172; 1.B.169.175; 1.B.169.240; 1.B.169.244; 1.B.172.228;1.B.172.229; 1.B.172.230; 1.B.172.231; 1.B.172.236; 1.B.172.237;1.B.172.238; 1.B.172.239; 1.B.172.154; 1.B.172.157; 1.B.172.166;1.B.172.169; 1.B.172.172; 1.B.172.175; 1.B.172.240; 1.B.172.244;1.B.175.228; 1.B.175.229; 1.B.175.230; 1.B.175.231; 1.B.175.236;1.B.175.237; 1.B.175.238; 1.B.175.239; 1.B.175.154; 1.B.175.157;1.B.175.166; 1.B.175.169; 1.B.175.172; 1.B.175.175; 1.B.175.240;1.B.175.244; 1.B.240.228; 1.B.240.229; 1.B.240.230; 1.B.240.231;1.B.240.236; 1.B.240.237; 1.B.240.238; 1.B.240.239; 1.B.240.154;1.B.240.157; 1.B.240.166; 1.B.240.169; 1.B.240.172; 1.B.240.175;1.B.240.240; 1.B.240.244; 1.B.244.228; 1.B.244.229; 1.B.244.230;1.B.244.231; 1.B.244.236; 1.B.244.237; 1.B.244.238; 1.B.244.239;1.B.244.154; 1.B.244.157; 1.B.244.166; 1.B.244.169; 1.B.244.172;1.B.244.175; 1.B.244.240; 1.B.244.244; Prodrugs of 1.D 1.D.228.228;1.D.228.229; 1.D.228.230; 1.D.228.231; 1.D.228.236; 1.D.228.237;1.D.228.238; 1.D.228.239; 1.D.228.154; 1.D.228.157; 1.D.228.166;1.D.228.169; 1.D.228.172; 1.D.228.175; 1.D.228.240; 1.D.228.244;1.D.229.228; 1.D.229.229; 1.D.229.230; 1.D.229.231; 1.D.229.236;1.D.229.237; 1.D.229.238; 1.D.229.239; 1.D.229.154; 1.D.229.157;1.D.229.166; 1.D.229.169; 1.D.229.172; 1.D.229.175; 1.D.229.240;1.D.229.244; 1.D.230.228; 1.D.230.229; 1.D.230.230; 1.D.230.231;1.D.230.236; 1.D.230.237; 1.D.230.238; 1.D.230.239; 1.D.230.154;1.D.230.157; 1.D.230.166; 1.D.230.169; 1.D.230.172; 1.D.230.175;1.D.230.240; 1.D.230.244; 1.D.231.228; 1.D.231.229; 1.D.231.230;1.D.231.231; 1.D.231.236; 1.D.231.237; 1.D.231.238; 1.D.231.239;1.D.231.154; 1.D.231.157; 1.D.231.166; 1.D.231.169; 1.D.231.172;1.D.231.175; 1.D.231.240; 1.D.231.244; 1.D.236.228; 1.D.236.229;1.D.236.230; 1.D.236.231; 1.D.236.236; 1.D.236.237; 1.D.236.238;1.D.236.239; 1.D.236.154; 1.D.236.157; 1.D.236.166; 1.D.236.169;1.D.236.172; 1.D.236.175; 1.D.236.240; 1.D.236.244; 1.D.237.228;1.D.237.229; 1.D.237.230; 1.D.237.231; 1.D.237.236; 1.D.237.237;1.D.237.238; 1.D.237.239; 1.D.237.154; 1.D.237.157; 1.D.237.166;1.D.237.169; 1.D.237.172; 1.D.237.175; 1.D.237.240; 1.D.237.244;1.D.238.228; 1.D.238.229; 1.D.238.230; 1.D.238.231; 1.D.238.236;1.D.238.237; 1.D.238.238; 1.D.238.239; 1.D.238.154; 1.D.238.157;1.D.238.166; 1.D.238.169; 1.D.238.172; 1.D.238.175; 1.D.238.240;1.D.238.244; 1.D.239.228; 1.D.239.229; 1.D.239.230; 1.D.239.231;1.D.239.236; 1.D.239.237; 1.D.239.238; 1.D.239.239; 1.D.239.154;1.D.239.157; 1.D.239.166; 1.D.239.169; 1.D.239.172; 1.D.239.175;1.D.239.240; 1.D.239.244; 1.D.154.228; 1.D.154.229; 1.D.154.230;1.D.154.231; 1.D.154.236; 1.D.154.237; 1.D.154.238; 1.D.154.239;1.D.154.154; 1.D.154.157; 1.D.154.166; 1.D.154.169; 1.D.154.172;1.D.154.175; 1.D.154.240; 1.D.154.244; 1.D.157.228; 1.D.157.229;1.D.157.230; 1.D.157.231; 1.D.157.236; 1.D.157.237; 1.D.157.238;1.D.157.239; 1.D.157.154; 1.D.157.157; 1.D.157.166; 1.D.157.169;1.D.157.172; 1.D.157.175; 1.D.157.240; 1.D.157.244; 1.D.166.228;1.D.166.229; 1.D.166.230; 1.D.166.231; 1.D.166.236; 1.D.166.237;1.D.166.238; 1.D.166.239; 1.D.166.154; 1.D.166.157; 1.D.166.166;1.D.166.169; 1.D.166.172; 1.D.166.175; 1.D.166.240; 1.D.166.244;1.D.169.228; 1.D.169.229; 1.D.169.230; 1.D.169.231; 1.D.169.236;1.D.169.237; 1.D.169.238; 1.D.169.239; 1.D.169.154; 1.D.169.157;1.D.169.166; 1.D.169.169; 1.D.169.172; 1.D.169.175; 1.D.169.240;1.D.169.244; 1.D.172.228; 1.D.172.229; 1.D.172.230; 1.D.172.231;1.D.172.236; 1.D.172.237; 1.D.172.238; 1.D.172.239; 1.D.172.154;1.D.172.157; 1.D.172.166; 1.D.172.169; 1.D.172.172; 1.D.172.175;1.D.172.240; 1.D.172.244; 1.D.175.228; 1.D.175.229; 1.D.175.230;1.D.175.231; 1.D.175.236; 1.D.175.237; 1.D.175.238; 1.D.175.239;1.D.175.154; 1.D.175.157; 1.D.175.166; 1.D.175.169; 1.D.175.172;1.D.175.175; 1.D.175.240; 1.D.175.244; 1.D.240.228; 1.D.240.229;1.D.240.230; 1.D.240.231; 1.D.240.236; 1.D.240.237; 1.D.240.238;1.D.240.239; 1.D.240.154; 1.D.240.157; 1.D.240.166; 1.D.240.169;1.D.240.172; 1.D.240.175; 1.D.240.240; 1.D.240.244; 1.D.244.228;1.D.244.229; 1.D.244.230; 1.D.244.231; 1.D.244.236; 1.D.244.237;1.D.244.238; 1.D.244.239; 1.D.244.154; 1.D.244.157; 1.D.244.166;1.D.244.169; 1.D.244.172; 1.D.244.175; 1.D.244.240; 1.D.244.244;Prodrugs of 1.E 1.E.228.228; 1.E.228.229; 1.E.228.230; 1.E.228.231;1.E.228.236; 1.E.228.237; 1.E.228.238; 1.E.228.239; 1.E.228.154;1.E.228.157; 1.E.228.166; 1.E.228.169; 1.E.228.172; 1.E.228.175;1.E.228.240; 1.E.228.244; 1.E.229.228; 1.E.229.229; 1.E.229.230;1.E.229.231; 1.E.229.236; 1.E.229.237; 1.E.229.238; 1.E.229.239;1.E.229.154; 1.E.229.157; 1.E.229.166; 1.E.229.169; 1.E.229.172;1.E.229.175; 1.E.229.240; 1.E.229.244; 1.E.230.228; 1.E.230.229;1.E.230.230; 1.E.230.231; 1.E.230.236; 1.E.230.237; 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1.G.169.230; 1.G.169.231; 1.G.169.236; 1.G.169.237;1.G.169.238; 1.G.169.239; 1.G.169.154; 1.G.169.157; 1.G.169.166;1.G.169.169; 1.G.169.172; 1.G.169.175; 1.G.169.240; 1.G.169.244;1.G.172.228; 1.G.172.229; 1.G.172.230; 1.G.172.231; 1.G.172.236;1.G.172.237; 1.G.172.238; 1.G.172.239; 1.G.172.154; 1.G.172.157;1.G.172.166; 1.G.172.169; 1.G.172.172; 1.G.172.175; 1.G.172.240;1.G.172.244; 1.G.175.228; 1.G.175.229; 1.G.175.230; 1.G.175.231;1.G.175.236; 1.G.175.237; 1.G.175.238; 1.G.175.239; 1.G.175.154;1.G.175.157; 1.G.175.166; 1.G.175.169; 1.G.175.172; 1.G.175.175;1.G.175.240; 1.G.175.244; 1.G.240.228; 1.G.240.229; 1.G.240.230;1.G.240.231; 1.G.240.236; 1.G.240.237; 1.G.240.238; 1.G.240.239;1.G.240.154; 1.G.240.157; 1.G.240.166; 1.G.240.169; 1.G.240.172;1.G.240.175; 1.G.240.240; 1.G.240.244; 1.G.244.228; 1.G.244.229;1.G.244.230; 1.G.244.231; 1.G.244.236; 1.G.244.237; 1.G.244.238;1.G.244.239; 1.G.244.154; 1.G.244.157; 1.G.244.166; 1.G.244.169;1.G.244.172; 1.G.244.175; 1.G.244.240; 1.G.244.244; Prodrugs of 1.I1.I.228.228; 1.I.228.229; 1.I.228.230; 1.I.228.231; 1.I.228.236;1.I.228.237; 1.I.228.238; 1.I.228.239; 1.I.228.154; 1.I.228.157;1.I.228.166; 1.I.228.169; 1.I.228.172; 1.I.228.175; 1.I.228.240;1.I.228.244; 1.I.229.228; 1.I.229.229; 1.I.229.230; 1.I.229.231;1.I.229.236; 1.I.229.237; 1.I.229.238; 1.I.229.239; 1.I.229.154;1.I.229.157; 1.I.229.166; 1.I.229.169; 1.I.229.172; 1.I.229.175;1.I.229.240; 1.I.229.244; 1.I.230.228; 1.I.230.229; 1.I.230.230;1.I.230.231; 1.I.230.236; 1.I.230.237; 1.I.230.238; 1.I.230.239;1.I.230.154; 1.I.230.157; 1.I.230.166; 1.I.230.169; 1.I.230.172;1.I.230.175; 1.I.230.240; 1.I.230.244; 1.I.231.228; 1.I.231.229;1.I.231.230; 1.I.231.231; 1.I.231.236; 1.I.231.237; 1.I.231.238;1.I.231.239; 1.I.231.154; 1.I.231.157; 1.I.231.166; 1.I.231.169;1.I.231.172; 1.I.231.175; 1.I.231.240; 1.I.231.244; 1.I.236.228;1.I.236.229; 1.I.236.230; 1.I.236.231; 1.I.236.236; 1.I.236.237;1.I.236.238; 1.I.236.239; 1.I.236.154; 1.I.236.157; 1.I.236.166;1.I.236.169; 1.I.236.172; 1.I.236.175; 1.I.236.240; 1.I.236.244;1.I.237.228; 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1.I.166.229; 1.I.166.230; 1.I.166.231; 1.I.166.236;1.I.166.237; 1.I.166.238; 1.I.166.239; 1.I.166.154; 1.I.166.157;1.I.166.166; 1.I.166.169; 1.I.166.172; 1.I.166.175; 1.I.166.240;1.I.166.244; 1.I.169.228; 1.I.169.229; 1.I.169.230; 1.I.169.231;1.I.169.236; 1.I.169.237; 1.I.169.238; 1.I.169.239; 1.I.169.154;1.I.169.157; 1.I.169.166; 1.I.169.169; 1.I.169.172; 1.I.169.175;1.I.169.240; 1.I.169.244; 1.I.172.228; 1.I.172.229; 1.I.172.230;1.I.172.231; 1.I.172.236; 1.I.172.237; 1.I.172.238; 1.I.172.239;1.I.172.154; 1.I.172.157; 1.I.172.166; 1.I.172.169; 1.I.172.172;1.I.172.175; 1.I.172.240; 1.I.172.244; 1.I.175.228; 1.I.175.229;1.I.175.230; 1.I.175.231; 1.I.175.236; 1.I.175.237; 1.I.175.238;1.I.175.239; 1.I.175.154; 1.I.175.157; 1.I.175.166; 1.I.175.169;1.I.175.172; 1.I.175.175; 1.I.175.240; 1.I.175.244; 1.I.240.228;1.I.240.229; 1.I.240.230; 1.I.240.231; 1.I.240.236; 1.I.240.237;1.I.240.238; 1.I.240.239; 1.I.240.154; 1.I.240.157; 1.I.240.166;1.I.240.169; 1.I.240.172; 1.I.240.175; 1.I.240.240; 1.I.240.244;1.I.244.228; 1.I.244.229; 1.I.244.230; 1.I.244.231; 1.I.244.236;1.I.244.237; 1.I.244.238; 1.I.244.239; 1.I.244.154; 1.I.244.157;1.I.244.166; 1.I.244.169; 1.I.244.172; 1.I.244.175; 1.I.244.240;1.I.244.244; Prodrugs of 1.J 1.J.228.228; 1.J.228.229; 1.J.228.230;1.J.228.231; 1.J.228.236; 1.J.228.237; 1.J.228.238; 1.J.228.239;1.J.228.154; 1.J.228.157; 1.J.228.166; 1.J.228.169; 1.J.228.172;1.J.228.175; 1.J.228.240; 1.J.228.244; 1.J.229.228; 1.J.229.229;1.J.229.230; 1.J.229.231; 1.J.229.236; 1.J.229.237; 1.J.229.238;1.J.229.239; 1.J.229.154; 1.J.229.157; 1.J.229.166; 1.J.229.169;1.J.229.172; 1.J.229.175; 1.J.229.240; 1.J.229.244; 1.J.230.228;1.J.230.229; 1.J.230.230; 1.J.230.231; 1.J.230.236; 1.J.230.237;1.J.230.238; 1.J.230.239; 1.J.230.154; 1.J.230.157; 1.J.230.166;1.J.230.169; 1.J.230.172; 1.J.230.175; 1.J.230.240; 1.J.230.244;1.J.231.228; 1.J.231.229; 1.J.231.230; 1.J.231.231; 1.J.231.236;1.J.231.237; 1.J.231.238; 1.J.231.239; 1.J.231.154; 1.J.231.157;1.J.231.166; 1.J.231.169; 1.J.231.172; 1.J.231.175; 1.J.231.240;1.J.231.244; 1.J.236.228; 1.J.236.229; 1.J.236.230; 1.J.236.231;1.J.236.236; 1.J.236.237; 1.J.236.238; 1.J.236.239; 1.J.236.154;1.J.236.157; 1.J.236.166; 1.J.236.169; 1.J.236.172; 1.J.236.175;1.J.236.240; 1.J.236.244; 1.J.237.228; 1.J.237.229; 1.J.237.230;1.J.237.231; 1.J.237.236; 1.J.237.237; 1.J.237.238; 1.J.237.239;1.J.237.154; 1.J.237.157; 1.J.237.166; 1.J.237.169; 1.J.237.172;1.J.237.175; 1.J.237.240; 1.J.237.244; 1.J.238.228; 1.J.238.229;1.J.238.230; 1.J.238.231; 1.J.238.236; 1.J.238.237; 1.J.238.238;1.J.238.239; 1.J.238.154; 1.J.238.157; 1.J.238.166; 1.J.238.169;1.J.238.172; 1.J.238.175; 1.J.238.240; 1.J.238.244; 1.J.239.228;1.J.239.229; 1.J.239.230; 1.J.239.231; 1.J.239.236; 1.J.239.237;1.J.239.238; 1.J.239.239; 1.J.239.154; 1.J.239.157; 1.J.239.166;1.J.239.169; 1.J.239.172; 1.J.239.175; 1.J.239.240; 1.J.239.244;1.J.154.228; 1.J.154.229; 1.J.154.230; 1.J.154.231; 1.J.154.236;1.J.154.237; 1.J.154.238; 1.J.154.239; 1.J.154.154; 1.J.154.157;1.J.154.166; 1.J.154.169; 1.J.154.172; 1.J.154.175; 1.J.154.240;1.J.154.244; 1.J.157.228; 1.J.157.229; 1.J.157.230; 1.J.157.231;1.J.157.236; 1.J.157.237; 1.J.157.238; 1.J.157.239; 1.J.157.154;1.J.157.157; 1.J.157.166; 1.J.157.169; 1.J.157.172; 1.J.157.175;1.J.157.240; 1.J.157.244; 1.J.166.228; 1.J.166.229; 1.J.166.230;1.J.166.231; 1.J.166.236; 1.J.166.237; 1.J.166.238; 1.J.166.239;1.J.166.154; 1.J.166.157; 1.J.166.166; 1.J.166.169; 1.J.166.172;1.J.166.175; 1.J.166.240; 1.J.166.244; 1.J.169.228; 1.J.169.229;1.J.169.230; 1.J.169.231; 1.J.169.236; 1.J.169.237; 1.J.169.238;1.J.169.239; 1.J.169.154; 1.J.169.157; 1.J.169.166; 1.J.169.169;1.J.169.172; 1.J.169.175; 1.J.169.240; 1.J.169.244; 1.J.172.228;1.J.172.229; 1.J.172.230; 1.J.172.231; 1.J.172.236; 1.J.172.237;1.J.172.238; 1.J.172.239; 1.J.172.154; 1.J.172.157; 1.J.172.166;1.J.172.169; 1.J.172.172; 1.J.172.175; 1.J.172.240; 1.J.172.244;1.J.175.228; 1.J.175.229; 1.J.175.230; 1.J.175.231; 1.J.175.236;1.J.175.237; 1.J.175.238; 1.J.175.239; 1.J.175.154; 1.J.175.157;1.J.175.166; 1.J.175.169; 1.J.175.172; 1.J.175.175; 1.J.175.240;1.J.175.244; 1.J.240.228; 1.J.240.229; 1.J.240.230; 1.J.240.231;1.J.240.236; 1.J.240.237; 1.J.240.238; 1.J.240.239; 1.J.240.154;1.J.240.157; 1.J.240.166; 1.J.240.169; 1.J.240.172; 1.J.240.175;1.J.240.240; 1.J.240.244; 1.J.244.228; 1.J.244.229; 1.J.244.230;1.J.244.231; 1.J.244.236; 1.J.244.237; 1.J.244.238; 1.J.244.239;1.J.244.154; 1.J.244.157; 1.J.244.166; 1.J.244.169; 1.J.244.172;1.J.244.175; 1.J.244.240; 1.J.244.244; Prodrugs of 1.L 1.L.228.228;1.L.228.229; 1.L.228.230; 1.L.228.231; 1.L.228.236; 1.L.228.237;1.L.228.238; 1.L.228.239; 1.L.228.154; 1.L.228.157; 1.L.228.166;1.L.228.169; 1.L.228.172; 1.L.228.175; 1.L.228.240; 1.L.228.244;1.L.229.228; 1.L.229.229; 1.L.229.230; 1.L.229.231; 1.L.229.236;1.L.229.237; 1.L.229.238; 1.L.229.239; 1.L.229.154; 1.L.229.157;1.L.229.166; 1.L.229.169; 1.L.229.172; 1.L.229.175; 1.L.229.240;1.L.229.244; 1.L.230.228; 1.L.230.229; 1.L.230.230; 1.L.230.231;1.L.230.236; 1.L.230.237; 1.L.230.238; 1.L.230.239; 1.L.230.154;1.L.230.157; 1.L.230.166; 1.L.230.169; 1.L.230.172; 1.L.230.175;1.L.230.240; 1.L.230.244; 1.L.231.228; 1.L.231.229; 1.L.231.230;1.L.231.231; 1.L.231.236; 1.L.231.237; 1.L.231.238; 1.L.231.239;1.L.231.154; 1.L.231.157; 1.L.231.166; 1.L.231.169; 1.L.231.172;1.L.231.175; 1.L.231.240; 1.L.231.244; 1.L.236.228; 1.L.236.229;1.L.236.230; 1.L.236.231; 1.L.236.236; 1.L.236.237; 1.L.236.238;1.L.236.239; 1.L.236.154; 1.L.236.157; 1.L.236.166; 1.L.236.169;1.L.236.172; 1.L.236.175; 1.L.236.240; 1.L.236.244; 1.L.237.228;1.L.237.229; 1.L.237.230; 1.L.237.231; 1.L.237.236; 1.L.237.237;1.L.237.238; 1.L.237.239; 1.L.237.154; 1.L.237.157; 1.L.237.166;1.L.237.169; 1.L.237.172; 1.L.237.175; 1.L.237.240; 1.L.237.244;1.L.238.228; 1.L.238.229; 1.L.238.230; 1.L.238.231; 1.L.238.236;1.L.238.237; 1.L.238.238; 1.L.238.239; 1.L.238.154; 1.L.238.157;1.L.238.166; 1.L.238.169; 1.L.238.172; 1.L.238.175; 1.L.238.240;1.L.238.244; 1.L.239.228; 1.L.239.229; 1.L.239.230; 1.L.239.231;1.L.239.236; 1.L.239.237; 1.L.239.238; 1.L.239.239; 1.L.239.154;1.L.239.157; 1.L.239.166; 1.L.239.169; 1.L.239.172; 1.L.239.175;1.L.239.240; 1.L.239.244; 1.L.154.228; 1.L.154.229; 1.L.154.230;1.L.154.231; 1.L.154.236; 1.L.154.237; 1.L.154.238; 1.L.154.239;1.L.154.154; 1.L.154.157; 1.L.154.166; 1.L.154.169; 1.L.154.172;1.L.154.175; 1.L.154.240; 1.L.154.244; 1.L.157.228; 1.L.157.229;1.L.157.230; 1.L.157.231; 1.L.157.236; 1.L.157.237; 1.L.157.238;1.L.157.239; 1.L.157.154; 1.L.157.157; 1.L.157.166; 1.L.157.169;1.L.157.172; 1.L.157.175; 1.L.157.240; 1.L.157.244; 1.L.166.228;1.L.166.229; 1.L.166.230; 1.L.166.231; 1.L.166.236; 1.L.166.237;1.L.166.238; 1.L.166.239; 1.L.166.154; 1.L.166.157; 1.L.166.166;1.L.166.169; 1.L.166.172; 1.L.166.175; 1.L.166.240; 1.L.166.244;1.L.169.228; 1.L.169.229; 1.L.169.230; 1.L.169.231; 1.L.169.236;1.L.169.237; 1.L.169.238; 1.L.169.239; 1.L.169.154; 1.L.169.157;1.L.169.166; 1.L.169.169; 1.L.169.172; 1.L.169.175; 1.L.169.240;1.L.169.244; 1.L.172.228; 1.L.172.229; 1.L.172.230; 1.L.172.231;1.L.172.236; 1.L.172.237; 1.L.172.238; 1.L.172.239; 1.L.172.154;1.L.172.157; 1.L.172.166; 1.L.172.169; 1.L.172.172; 1.L.172.175;1.L.172.240; 1.L.172.244; 1.L.175.228; 1.L.175.229; 1.L.175.230;1.L.175.231; 1.L.175.236; 1.L.175.237; 1.L.175.238; 1.L.175.239;1.L.175.154; 1.L.175.157; 1.L.175.166; 1.L.175.169; 1.L.175.172;1.L.175.175; 1.L.175.240; 1.L.175.244; 1.L.240.228; 1.L.240.229;1.L.240.230; 1.L.240.231; 1.L.240.236; 1.L.240.237; 1.L.240.238;1.L.240.239; 1.L.240.154; 1.L.240.157; 1.L.240.166; 1.L.240.169;1.L.240.172; 1.L.240.175; 1.L.240.240; 1.L.240.244; 1.L.244.228;1.L.244.229; 1.L.244.230; 1.L.244.231; 1.L.244.236; 1.L.244.237;1.L.244.238; 1.L.244.239; 1.L.244.154; 1.L.244.157; 1.L.244.166;1.L.244.169; 1.L.244.172; 1.L.244.175; 1.L.244.240; 1.L.244.244;Prodrugs of 1.O 1.O.228.228; 1.O.228.229; 1.O.228.230; 1.O.228.231;1.O.228.236; 1.O.228.237; 1.O.228.238; 1.O.228.239; 1.O.228.154;1.O.228.157; 1.O.228.166; 1.O.228.169; 1.O.228.172; 1.O.228.175;1.O.228.240; 1.O.228.244; 1.O.229.228; 1.O.229.229; 1.O.229.230;1.O.229.231; 1.O.229.236; 1.O.229.237; 1.O.229.238; 1.O.229.239;1.O.229.154; 1.O.229.157; 1.O.229.166; 1.O.229.169; 1.O.229.172;1.O.229.175; 1.O.229.240; 1.O.229.244; 1.O.230.228; 1.O.230.229;1.O.230.230; 1.O.230.231; 1.O.230.236; 1.O.230.237; 1.O.230.238;1.O.230.239; 1.O.230.154; 1.O.230.157; 1.O.230.166; 1.O.230.169;1.O.230.172; 1.O.230.175; 1.O.230.240; 1.O.230.244; 1.O.231.228;1.O.231.229; 1.O.231.230; 1.O.231.231; 1.O.231.236; 1.O.231.237;1.O.231.238; 1.O.231.239; 1.O.231.154; 1.O.231.157; 1.O.231.166;1.O.231.169; 1.O.231.172; 1.O.231.175; 1.O.231.240; 1.O.231.244;1.O.236.228; 1.O.236.229; 1.O.236.230; 1.O.236.231; 1.O.236.236;1.O.236.237; 1.O.236.238; 1.O.236.239; 1.O.236.154; 1.O.236.157;1.O.236.166; 1.O.236.169; 1.O.236.172; 1.O.236.175; 1.O.236.240;1.O.236.244; 1.O.237.228; 1.O.237.229; 1.O.237.230; 1.O.237.231;1.O.237.236; 1.O.237.237; 1.O.237.238; 1.O.237.239; 1.O.237.154;1.O.237.157; 1.O.237.166; 1.O.237.169; 1.O.237.172; 1.O.237.175;1.O.237.240; 1.O.237.244; 1.O.238.228; 1.O.238.229; 1.O.238.230;1.O.238.231; 1.O.238.236; 1.O.238.237; 1.O.238.238; 1.O.238.239;1.O.238.154; 1.O.238.157; 1.O.238.166; 1.O.238.169; 1.O.238.172;1.O.238.175; 1.O.238.240; 1.O.238.244; 1.O.239.228; 1.O.239.229;1.O.239.230; 1.O.239.231; 1.O.239.236; 1.O.239.237; 1.O.239.238;1.O.239.239; 1.O.239.154; 1.O.239.157; 1.O.239.166; 1.O.239.169;1.O.239.172; 1.O.239.175; 1.O.239.240; 1.O.239.244; 1.O.154.228;1.O.154.229; 1.O.154.230; 1.O.154.231; 1.O.154.236; 1.O.154.237;1.O.154.238; 1.O.154.239; 1.O.154.154; 1.O.154.157; 1.O.154.166;1.O.154.169; 1.O.154.172; 1.O.154.175; 1.O.154.240; 1.O.154.244;1.O.157.228; 1.O.157.229; 1.O.157.230; 1.O.157.231; 1.O.157.236;1.O.157.237; 1.O.157.238; 1.O.157.239; 1.O.157.154; 1.O.157.157;1.O.157.166; 1.O.157.169; 1.O.157.172; 1.O.157.175; 1.O.157.240;1.O.157.244; 1.O.166.228; 1.O.166.229; 1.O.166.230; 1.O.166.231;1.O.166.236; 1.O.166.237; 1.O.166.238; 1.O.166.239; 1.O.166.154;1.O.166.157; 1.O.166.166; 1.O.166.169; 1.O.166.172; 1.O.166.175;1.O.166.240; 1.O.166.244; 1.O.169.228; 1.O.169.229; 1.O.169.230;1.O.169.231; 1.O.169.236; 1.O.169.237; 1.O.169.238; 1.O.169.239;1.O.169.154; 1.O.169.157; 1.O.169.166; 1.O.169.169; 1.O.169.172;1.O.169.175; 1.O.169.240; 1.O.169.244; 1.O.172.228; 1.O.172.229;1.O.172.230; 1.O.172.231; 1.O.172.236; 1.O.172.237; 1.O.172.238;1.O.172.239; 1.O.172.154; 1.O.172.157; 1.O.172.166; 1.O.172.169;1.O.172.172; 1.O.172.175; 1.O.172.240; 1.O.172.244; 1.O.175.228;1.O.175.229; 1.O.175.230; 1.O.175.231; 1.O.175.236; 1.O.175.237;1.O.175.238; 1.O.175.239; 1.O.175.154; 1.O.175.157; 1.O.175.166;1.O.175.169; 1.O.175.172; 1.O.175.175; 1.O.175.240; 1.O.175.244;1.O.240.228; 1.O.240.229; 1.O.240.230; 1.O.240.231; 1.O.240.236;1.O.240.237; 1.O.240.238; 1.O.240.239; 1.O.240.154; 1.O.240.157;1.O.240.166; 1.O.240.169; 1.O.240.172; 1.O.240.175; 1.O.240.240;1.O.240.244; 1.O.244.228; 1.O.244.229; 1.O.244.230; 1.O.244.231;1.O.244.236; 1.O.244.237; 1.O.244.238; 1.O.244.239; 1.O.244.154;1.O.244.157; 1.O.244.166; 1.O.244.169; 1.O.244.172; 1.O.244.175;1.O.244.240; 1.O.244.244; Prodrugs of 1.P 1.P.228.228; 1.P.228.229;1.P.228.230; 1.P.228.231; 1.P.228.236; 1.P.228.237; 1.P.228.238;1.P.228.239; 1.P.228.154; 1.P.228.157; 1.P.228.166; 1.P.228.169;1.P.228.172; 1.P.228.175; 1.P.228.240; 1.P.228.244; 1.P.229.228;1.P.229.229; 1.P.229.230; 1.P.229.231; 1.P.229.236; 1.P.229.237;1.P.229.238; 1.P.229.239; 1.P.229.154; 1.P.229.157; 1.P.229.166;1.P.229.169; 1.P.229.172; 1.P.229.175; 1.P.229.240; 1.P.229.244;1.P.230.228; 1.P.230.229; 1.P.230.230; 1.P.230.231; 1.P.230.236;1.P.230.237; 1.P.230.238; 1.P.230.239; 1.P.230.154; 1.P.230.157;1.P.230.166; 1.P.230.169; 1.P.230.172; 1.P.230.175; 1.P.230.240;1.P.230.244; 1.P.231.228; 1.P.231.229; 1.P.231.230; 1.P.231.231;1.P.231.236; 1.P.231.237; 1.P.231.238; 1.P.231.239; 1.P.231.154;1.P.231.157; 1.P.231.166; 1.P.231.169; 1.P.231.172; 1.P.231.175;1.P.231.240; 1.P.231.244; 1.P.236.228; 1.P.236.229; 1.P.236.230;1.P.236.231; 1.P.236.236; 1.P.236.237; 1.P.236.238; 1.P.236.239;1.P.236.154; 1.P.236.157; 1.P.236.166; 1.P.236.169; 1.P.236.172;1.P.236.175; 1.P.236.240; 1.P.236.244; 1.P.237.228; 1.P.237.229;1.P.237.230; 1.P.237.231; 1.P.237.236; 1.P.237.237; 1.P.237.238;1.P.237.239; 1.P.237.154; 1.P.237.157; 1.P.237.166; 1.P.237.169;1.P.237.172; 1.P.237.175; 1.P.237.240; 1.P.237.244; 1.P.238.228;1.P.238.229; 1.P.238.230; 1.P.238.231; 1.P.238.236; 1.P.238.237;1.P.238.238; 1.P.238.239; 1.P.238.154; 1.P.238.157; 1.P.238.166;1.P.238.169; 1.P.238.172; 1.P.238.175; 1.P.238.240; 1.P.238.244;1.P.239.228; 1.P.239.229; 1.P.239.230; 1.P.239.231; 1.P.239.236;1.P.239.237; 1.P.239.238; 1.P.239.239; 1.P.239.154; 1.P.239.157;1.P.239.166; 1.P.239.169; 1.P.239.172; 1.P.239.175; 1.P.239.240;1.P.239.244; 1.P.154.228; 1.P.154.229; 1.P.154.230; 1.P.154.231;1.P.154.236; 1.P.154.237; 1.P.154.238; 1.P.154.239; 1.P.154.154;1.P.154.157; 1.P.154.166; 1.P.154.169; 1.P.154.172; 1.P.154.175;1.P.154.240; 1.P.154.244; 1.P.157.228; 1.P.157.229; 1.P.157.230;1.P.157.231; 1.P.157.236; 1.P.157.237; 1.P.157.238; 1.P.157.239;1.P.157.154; 1.P.157.157; 1.P.157.166; 1.P.157.169; 1.P.157.172;1.P.157.175; 1.P.157.240; 1.P.157.244; 1.P.166.228; 1.P.166.229;1.P.166.230; 1.P.166.231; 1.P.166.236; 1.P.166.237; 1.P.166.238;1.P.166.239; 1.P.166.154; 1.P.166.157; 1.P.166.166; 1.P.166.169;1.P.166.172; 1.P.166.175; 1.P.166.240; 1.P.166.244; 1.P.169.228;1.P.169.229; 1.P.169.230; 1.P.169.231; 1.P.169.236; 1.P.169.237;1.P.169.238; 1.P.169.239; 1.P.169.154; 1.P.169.157; 1.P.169.166;1.P.169.169; 1.P.169.172; 1.P.169.175; 1.P.169.240; 1.P.169.244;1.P.172.228; 1.P.172.229; 1.P.172.230; 1.P.172.231; 1.P.172.236;1.P.172.237; 1.P.172.238; 1.P.172.239; 1.P.172.154; 1.P.172.157;1.P.172.166; 1.P.172.169; 1.P.172.172; 1.P.172.175; 1.P.172.240;1.P.172.244; 1.P.175.228; 1.P.175.229; 1.P.175.230; 1.P.175.231;1.P.175.236; 1.P.175.237; 1.P.175.238; 1.P.175.239; 1.P.175.154;1.P.175.157; 1.P.175.166; 1.P.175.169; 1.P.175.172; 1.P.175.175;1.P.175.240; 1.P.175.244; 1.P.240.228; 1.P.240.229; 1.P.240.230;1.P.240.231; 1.P.240.236; 1.P.240.237; 1.P.240.238; 1.P.240.239;1.P.240.154; 1.P.240.157; 1.P.240.166; 1.P.240.169; 1.P.240.172;1.P.240.175; 1.P.240.240; 1.P.240.244; 1.P.244.228; 1.P.244.229;1.P.244.230; 1.P.244.231; 1.P.244.236; 1.P.244.237; 1.P.244.238;1.P.244.239; 1.P.244.154; 1.P.244.157; 1.P.244.166; 1.P.244.169;1.P.244.172; 1.P.244.175; 1.P.244.240; 1.P.244.244; Prodrugs of 1.U1.U.228.228; 1.U.228.229; 1.U.228.230; 1.U.228.231; 1.U.228.236;1.U.228.237; 1.U.228.238; 1.U.228.239; 1.U.228.154; 1.U.228.157;1.U.228.166; 1.U.228.169; 1.U.228.172; 1.U.228.175; 1.U.228.240;1.U.228.244; 1.U.229.228; 1.U.229.229; 1.U.229.230; 1.U.229.231;1.U.229.236; 1.U.229.237; 1.U.229.238; 1.U.229.239; 1.U.229.154;1.U.229.157; 1.U.229.166; 1.U.229.169; 1.U.229.172; 1.U.229.175;1.U.229.240; 1.U.229.244; 1.U.230.228; 1.U.230.229; 1.U.230.230;1.U.230.231; 1.U.230.236; 1.U.230.237; 1.U.230.238; 1.U.230.239;1.U.230.154; 1.U.230.157; 1.U.230.166; 1.U.230.169; 1.U.230.172;1.U.230.175; 1.U.230.240; 1.U.230.244; 1.U.231.228; 1.U.231.229;1.U.231.230; 1.U.231.231; 1.U.231.236; 1.U.231.237; 1.U.231.238;1.U.231.239; 1.U.231.154; 1.U.231.157; 1.U.231.166; 1.U.231.169;1.U.231.172; 1.U.231.175; 1.U.231.240; 1.U.231.244; 1.U.236.228;1.U.236.229; 1.U.236.230; 1.U.236.231; 1.U.236.236; 1.U.236.237;1.U.236.238; 1.U.236.239; 1.U.236.154; 1.U.236.157; 1.U.236.166;1.U.236.169; 1.U.236.172; 1.U.236.175; 1.U.236.240; 1.U.236.244;1.U.237.228; 1.U.237.229; 1.U.237.230; 1.U.237.231; 1.U.237.236;1.U.237.237; 1.U.237.238; 1.U.237.239; 1.U.237.154; 1.U.237.157;1.U.237.166; 1.U.237.169; 1.U.237.172; 1.U.237.175; 1.U.237.240;1.U.237.244; 1.U.238.228; 1.U.238.229; 1.U.238.230; 1.U.238.231;1.U.238.236; 1.U.238.237; 1.U.238.238; 1.U.238.239; 1.U.238.154;1.U.238.157; 1.U.238.166; 1.U.238.169; 1.U.238.172; 1.U.238.175;1.U.238.240; 1.U.238.244; 1.U.239.228; 1.U.239.229; 1.U.239.230;1.U.239.231; 1.U.239.236; 1.U.239.237; 1.U.239.238; 1.U.239.239;1.U.239.154; 1.U.239.157; 1.U.239.166; 1.U.239.169; 1.U.239.172;1.U.239.175; 1.U.239.240; 1.U.239.244; 1.U.154.228; 1.U.154.229;1.U.154.230; 1.U.154.231; 1.U.154.236; 1.U.154.237; 1.U.154.238;1.U.154.239; 1.U.154.154; 1.U.154.157; 1.U.154.166; 1.U.154.169;1.U.154.172; 1.U.154.175; 1.U.154.240; 1.U.154.244; 1.U.157.228;1.U.157.229; 1.U.157.230; 1.U.157.231; 1.U.157.236; 1.U.157.237;1.U.157.238; 1.U.157.239; 1.U.157.154; 1.U.157.157; 1.U.157.166;1.U.157.169; 1.U.157.172; 1.U.157.175; 1.U.157.240; 1.U.157.244;1.U.166.228; 1.U.166.229; 1.U.166.230; 1.U.166.231; 1.U.166.236;1.U.166.237; 1.U.166.238; 1.U.166.239; 1.U.166.154; 1.U.166.157;1.U.166.166; 1.U.166.169; 1.U.166.172; 1.U.166.175; 1.U.166.240;1.U.166.244; 1.U.169.228; 1.U.169.229; 1.U.169.230; 1.U.169.231;1.U.169.236; 1.U.169.237; 1.U.169.238; 1.U.169.239; 1.U.169.154;1.U.169.157; 1.U.169.166; 1.U.169.169; 1.U.169.172; 1.U.169.175;1.U.169.240; 1.U.169.244; 1.U.172.228; 1.U.172.229; 1.U.172.230;1.U.172.231; 1.U.172.236; 1.U.172.237; 1.U.172.238; 1.U.172.239;1.U.172.154; 1.U.172.157; 1.U.172.166; 1.U.172.169; 1.U.172.172;1.U.172.175; 1.U.172.240; 1.U.172.244; 1.U.175.228; 1.U.175.229;1.U.175.230; 1.U.175.231; 1.U.175.236; 1.U.175.237; 1.U.175.238;1.U.175.239; 1.U.175.154; 1.U.175.157; 1.U.175.166; 1.U.175.169;1.U.175.172; 1.U.175.175; 1.U.175.240; 1.U.175.244; 1.U.240.228;1.U.240.229; 1.U.240.230; 1.U.240.231; 1.U.240.236; 1.U.240.237;1.U.240.238; 1.U.240.239; 1.U.240.154; 1.U.240.157; 1.U.240.166;1.U.240.169; 1.U.240.172; 1.U.240.175; 1.U.240.240; 1.U.240.244;1.U.244.228; 1.U.244.229; 1.U.244.230; 1.U.244.231; 1.U.244.236;1.U.244.237; 1.U.244.238; 1.U.244.239; 1.U.244.154; 1.U.244.157;1.U.244.166; 1.U.244.169; 1.U.244.172; 1.U.244.175; 1.U.244.240;1.U.244.244; Prodrugs of 1.W 1.W.228.228; 1.W.228.229; 1.W.228.230;1.W.228.231; 1.W.228.236; 1.W.228.237; 1.W.228.238; 1.W.228.239;1.W.228.154; 1.W.228.157; 1.W.228.166; 1.W.228.169; 1.W.228.172;1.W.228.175; 1.W.228.240; 1.W.228.244; 1.W.229.228; 1.W.229.229;1.W.229.230; 1.W.229.231; 1.W.229.236; 1.W.229.237; 1.W.229.238;1.W.229.239; 1.W.229.154; 1.W.229.157; 1.W.229.166; 1.W.229.169;1.W.229.172; 1.W.229.175; 1.W.229.240; 1.W.229.244; 1.W.230.228;1.W.230.229; 1.W.230.230; 1.W.230.231; 1.W.230.236; 1.W.230.237;1.W.230.238; 1.W.230.239; 1.W.230.154; 1.W.230.157; 1.W.230.166;1.W.230.169; 1.W.230.172; 1.W.230.175; 1.W.230.240; 1.W.230.244;1.W.231.228; 1.W.231.229; 1.W.231.230; 1.W.231.231; 1.W.231.236;1.W.231.237; 1.W.231.238; 1.W.231.239; 1.W.231.154; 1.W.231.157;1.W.231.166; 1.W.231.169; 1.W.231.172; 1.W.231.175; 1.W.231.240;1.W.231.244; 1.W.236.228; 1.W.236.229; 1.W.236.230; 1.W.236.231;1.W.236.236; 1.W.236.237; 1.W.236.238; 1.W.236.239; 1.W.236.154;1.W.236.157; 1.W.236.166; 1.W.236.169; 1.W.236.172; 1.W.236.175;1.W.236.240; 1.W.236.244; 1.W.237.228; 1.W.237.229; 1.W.237.230;1.W.237.231; 1.W.237.236; 1.W.237.237; 1.W.237.238; 1.W.237.239;1.W.237.154; 1.W.237.157; 1.W.237.166; 1.W.237.169; 1.W.237.172;1.W.237.175; 1.W.237.240; 1.W.237.244; 1.W.238.228; 1.W.238.229;1.W.238.230; 1.W.238.231; 1.W.238.236; 1.W.238.237; 1.W.238.238;1.W.238.239; 1.W.238.154; 1.W.238.157; 1.W.238.166; 1.W.238.169;1.W.238.172; 1.W.238.175; 1.W.238.240; 1.W.238.244; 1.W.239.228;1.W.239.229; 1.W.239.230; 1.W.239.231; 1.W.239.236; 1.W.239.237;1.W.239.238; 1.W.239.239; 1.W.239.154; 1.W.239.157; 1.W.239.166;1.W.239.169; 1.W.239.172; 1.W.239.175; 1.W.239.240; 1.W.239.244;1.W.154.228; 1.W.154.229; 1.W.154.230; 1.W.154.231; 1.W.154.236;1.W.154.237; 1.W.154.238; 1.W.154.239; 1.W.154.154; 1.W.154.157;1.W.154.166; 1.W.154.169; 1.W.154.172; 1.W.154.175; 1.W.154.240;1.W.154.244; 1.W.157.228; 1.W.157.229; 1.W.157.230; 1.W.157.231;1.W.157.236; 1.W.157.237; 1.W.157.238; 1.W.157.239; 1.W.157.154;1.W.157.157; 1.W.157.166; 1.W.157.169; 1.W.157.172; 1.W.157.175;1.W.157.240; 1.W.157.244; 1.W.166.228; 1.W.166.229; 1.W.166.230;1.W.166.231; 1.W.166.236; 1.W.166.237; 1.W.166.238; 1.W.166.239;1.W.166.154; 1.W.166.157; 1.W.166.166; 1.W.166.169; 1.W.166.172;1.W.166.175; 1.W.166.240; 1.W.166.244; 1.W.169.228; 1.W.169.229;1.W.169.230; 1.W.169.231; 1.W.169.236; 1.W.169.237; 1.W.169.238;1.W.169.239; 1.W.169.154; 1.W.169.157; 1.W.169.166; 1.W.169.169;1.W.169.172; 1.W.169.175; 1.W.169.240; 1.W.169.244; 1.W.172.228;1.W.172.229; 1.W.172.230; 1.W.172.231; 1.W.172.236; 1.W.172.237;1.W.172.238; 1.W.172.239; 1.W.172.154; 1.W.172.157; 1.W.172.166;1.W.172.169; 1.W.172.172; 1.W.172.175; 1.W.172.240; 1.W.172.244;1.W.175.228; 1.W.175.229; 1.W.175.230; 1.W.175.231; 1.W.175.236;1.W.175.237; 1.W.175.238; 1.W.175.239; 1.W.175.154; 1.W.175.157;1.W.175.166; 1.W.175.169; 1.W.175.172; 1.W.175.175; 1.W.175.240;1.W.175.244; 1.W.240.228; 1.W.240.229; 1.W.240.230; 1.W.240.231;1.W.240.236; 1.W.240.237; 1.W.240.238; 1.W.240.239; 1.W.240.154;1.W.240.157; 1.W.240.166; 1.W.240.169; 1.W.240.172; 1.W.240.175;1.W.240.240; 1.W.240.244; 1.W.244.228; 1.W.244.229; 1.W.244.230;1.W.244.231; 1.W.244.236; 1.W.244.237; 1.W.244.238; 1.W.244.239;1.W.244.154; 1.W.244.157; 1.W.244.166; 1.W.244.169; 1.W.244.172;1.W.244.175; 1.W.244.240; 1.W.244.244; Prodrugs of 1.Y 1.Y.228.228;1.Y.228.229; 1.Y.228.230; 1.Y.228.231; 1.Y.228.236; 1.Y.228.237;1.Y.228.238; 1.Y.228.239; 1.Y.228.154; 1.Y.228.157; 1.Y.228.166;1.Y.228.169; 1.Y.228.172; 1.Y.228.175; 1.Y.228.240; 1.Y.228.244;1.Y.229.228; 1.Y.229.229; 1.Y.229.230; 1.Y.229.231; 1.Y.229.236;1.Y.229.237; 1.Y.229.238; 1.Y.229.239; 1.Y.229.154; 1.Y.229.157;1.Y.229.166; 1.Y.229.169; 1.Y.229.172; 1.Y.229.175; 1.Y.229.240;1.Y.229.244; 1.Y.230.228; 1.Y.230.229; 1.Y.230.230; 1.Y.230.231;1.Y.230.236; 1.Y.230.237; 1.Y.230.238; 1.Y.230.239; 1.Y.230.154;1.Y.230.157; 1.Y.230.166; 1.Y.230.169; 1.Y.230.172; 1.Y.230.175;1.Y.230.240; 1.Y.230.244; 1.Y.231.228; 1.Y.231.229; 1.Y.231.230;1.Y.231.231; 1.Y.231.236; 1.Y.231.237; 1.Y.231.238; 1.Y.231.239;1.Y.231.154; 1.Y.231.157; 1.Y.231.166; 1.Y.231.169; 1.Y.231.172;1.Y.231.175; 1.Y.231.240; 1.Y.231.244; 1.Y.236.228; 1.Y.236.229;1.Y.236.230; 1.Y.236.231; 1.Y.236.236; 1.Y.236.237; 1.Y.236.238;1.Y.236.239; 1.Y.236.154; 1.Y.236.157; 1.Y.236.166; 1.Y.236.169;1.Y.236.172; 1.Y.236.175; 1.Y.236.240; 1.Y.236.244; 1.Y.237.228;1.Y.237.229; 1.Y.237.230; 1.Y.237.231; 1.Y.237.236; 1.Y.237.237;1.Y.237.238; 1.Y.237.239; 1.Y.237.154; 1.Y.237.157; 1.Y.237.166;1.Y.237.169; 1.Y.237.172; 1.Y.237.175; 1.Y.237.240; 1.Y.237.244;1.Y.238.228; 1.Y.238.229; 1.Y.238.230; 1.Y.238.231; 1.Y.238.236;1.Y.238.237; 1.Y.238.238; 1.Y.238.239; 1.Y.238.154; 1.Y.238.157;1.Y.238.166; 1.Y.238.169; 1.Y.238.172; 1.Y.238.175; 1.Y.238.240;1.Y.238.244; 1.Y.239.228; 1.Y.239.229; 1.Y.239.230; 1.Y.239.231;1.Y.239.236; 1.Y.239.237; 1.Y.239.238; 1.Y.239.239; 1.Y.239.154;1.Y.239.157; 1.Y.239.166; 1.Y.239.169; 1.Y.239.172; 1.Y.239.175;1.Y.239.240; 1.Y.239.244; 1.Y.154.228; 1.Y.154.229; 1.Y.154.230;1.Y.154.231; 1.Y.154.236; 1.Y.154.237; 1.Y.154.238; 1.Y.154.239;1.Y.154.154; 1.Y.154.157; 1.Y.154.166; 1.Y.154.169; 1.Y.154.172;1.Y.154.175; 1.Y.154.240; 1.Y.154.244; 1.Y.157.228; 1.Y.157.229;1.Y.157.230; 1.Y.157.231; 1.Y.157.236; 1.Y.157.237; 1.Y.157.238;1.Y.157.239; 1.Y.157.154; 1.Y.157.157; 1.Y.157.166; 1.Y.157.169;1.Y.157.172; 1.Y.157.175; 1.Y.157.240; 1.Y.157.244; 1.Y.166.228;1.Y.166.229; 1.Y.166.230; 1.Y.166.231; 1.Y.166.236; 1.Y.166.237;1.Y.166.238; 1.Y.166.239; 1.Y.166.154; 1.Y.166.157; 1.Y.166.166;1.Y.166.169; 1.Y.166.172; 1.Y.166.175; 1.Y.166.240; 1.Y.166.244;1.Y.169.228; 1.Y.169.229; 1.Y.169.230; 1.Y.169.231; 1.Y.169.236;1.Y.169.237; 1.Y.169.238; 1.Y.169.239; 1.Y.169.154; 1.Y.169.157;1.Y.169.166; 1.Y.169.169; 1.Y.169.172; 1.Y.169.175; 1.Y.169.240;1.Y.169.244; 1.Y.172.228; 1.Y.172.229; 1.Y.172.230; 1.Y.172.231;1.Y.172.236; 1.Y.172.237; 1.Y.172.238; 1.Y.172.239; 1.Y.172.154;1.Y.172.157; 1.Y.172.166; 1.Y.172.169; 1.Y.172.172; 1.Y.172.175;1.Y.172.240; 1.Y.172.244; 1.Y.175.228; 1.Y.175.229; 1.Y.175.230;1.Y.175.231; 1.Y.175.236; 1.Y.175.237; 1.Y.175.238; 1.Y.175.239;1.Y.175.154; 1.Y.175.157; 1.Y.175.166; 1.Y.175.169; 1.Y.175.172;1.Y.175.175; 1.Y.175.240; 1.Y.175.244; 1.Y.240.228; 1.Y.240.229;1.Y.240.230; 1.Y.240.231; 1.Y.240.236; 1.Y.240.237; 1.Y.240.238;1.Y.240.239; 1.Y.240.154; 1.Y.240.157; 1.Y.240.166; 1.Y.240.169;1.Y.240.172; 1.Y.240.175; 1.Y.240.240; 1.Y.240.244; 1.Y.244.228;1.Y.244.229; 1.Y.244.230; 1.Y.244.231; 1.Y.244.236; 1.Y.244.237;1.Y.244.238; 1.Y.244.239; 1.Y.244.154; 1.Y.244.157; 1.Y.244.166;1.Y.244.169; 1.Y.244.172; 1.Y.244.175; 1.Y.244.240; 1.Y.244.244;Prodrugs of 2.B 2.B.228.228; 2.B.228.229; 2.B.228.230; 2.B.228.231;2.B.228.236; 2.B.228.237; 2.B.228.238; 2.B.228.239; 2.B.228.154;2.B.228.157; 2.B.228.166; 2.B.228.169; 2.B.228.172; 2.B.228.175;2.B.228.240; 2.B.228.244; 2.B.229.228; 2.B.229.229; 2.B.229.230;2.B.229.231; 2.B.229.236; 2.B.229.237; 2.B.229.238; 2.B.229.239;2.B.229.154; 2.B.229.157; 2.B.229.166; 2.B.229.169; 2.B.229.172;2.B.229.175; 2.B.229.240; 2.B.229.244; 2.B.230.228; 2.B.230.229;2.B.230.230; 2.B.230.231; 2.B.230.236; 2.B.230.237; 2.B.230.238;2.B.230.239; 2.B.230.154; 2.B.230.157; 2.B.230.166; 2.B.230.169;2.B.230.172; 2.B.230.175; 2.B.230.240; 2.B.230.244; 2.B.231.228;2.B.231.229; 2.B.231.230; 2.B.231.231; 2.B.231.236; 2.B.231.237;2.B.231.238; 2.B.231.239; 2.B.231.154; 2.B.231.157; 2.B.231.166;2.B.231.169; 2.B.231.172; 2.B.231.175; 2.B.231.240; 2.B.231.244;2.B.236.228; 2.B.236.229; 2.B.236.230; 2.B.236.231; 2.B.236.236;2.B.236.237; 2.B.236.238; 2.B.236.239; 2.B.236.154; 2.B.236.157;2.B.236.166; 2.B.236.169; 2.B.236.172; 2.B.236.175; 2.B.236.240;2.B.236.244; 2.B.237.228; 2.B.237.229; 2.B.237.230; 2.B.237.231;2.B.237.236; 2.B.237.237; 2.B.237.238; 2.B.237.239; 2.B.237.154;2.B.237.157; 2.B.237.166; 2.B.237.169; 2.B.237.172; 2.B.237.175;2.B.237.240; 2.B.237.244; 2.B.238.228; 2.B.238.229; 2.B.238.230;2.B.238.231; 2.B.238.236; 2.B.238.237; 2.B.238.238; 2.B.238.239;2.B.238.154; 2.B.238.157; 2.B.238.166; 2.B.238.169; 2.B.238.172;2.B.238.175; 2.B.238.240; 2.B.238.244; 2.B.239.228; 2.B.239.229;2.B.239.230; 2.B.239.231; 2.B.239.236; 2.B.239.237; 2.B.239.238;2.B.239.239; 2.B.239.154; 2.B.239.157; 2.B.239.166; 2.B.239.169;2.B.239.172; 2.B.239.175; 2.B.239.240; 2.B.239.244; 2.B.154.228;2.B.154.229; 2.B.154.230; 2.B.154.231; 2.B.154.236; 2.B.154.237;2.B.154.238; 2.B.154.239; 2.B.154.154; 2.B.154.157; 2.B.154.166;2.B.154.169; 2.B.154.172; 2.B.154.175; 2.B.154.240; 2.B.154.244;2.B.157.228; 2.B.157.229; 2.B.157.230; 2.B.157.231; 2.B.157.236;2.B.157.237; 2.B.157.238; 2.B.157.239; 2.B.157.154; 2.B.157.157;2.B.157.166; 2.B.157.169; 2.B.157.172; 2.B.157.175; 2.B.157.240;2.B.157.244; 2.B.166.228; 2.B.166.229; 2.B.166.230; 2.B.166.231;2.B.166.236; 2.B.166.237; 2.B.166.238; 2.B.166.239; 2.B.166.154;2.B.166.157; 2.B.166.166; 2.B.166.169; 2.B.166.172; 2.B.166.175;2.B.166.240; 2.B.166.244; 2.B.169.228; 2.B.169.229; 2.B.169.230;2.B.169.231; 2.B.169.236; 2.B.169.237; 2.B.169.238; 2.B.169.239;2.B.169.154; 2.B.169.157; 2.B.169.166; 2.B.169.169; 2.B.169.172;2.B.169.175; 2.B.169.240; 2.B.169.244; 2.B.172.228; 2.B.172.229;2.B.172.230; 2.B.172.231; 2.B.172.236; 2.B.172.237; 2.B.172.238;2.B.172.239; 2.B.172.154; 2.B.172.157; 2.B.172.166; 2.B.172.169;2.B.172.172; 2.B.172.175; 2.B.172.240; 2.B.172.244; 2.B.175.228;2.B.175.229; 2.B.175.230; 2.B.175.231; 2.B.175.236; 2.B.175.237;2.B.175.238; 2.B.175.239; 2.B.175.154; 2.B.175.157; 2.B.175.166;2.B.175.169; 2.B.175.172; 2.B.175.175; 2.B.175.240; 2.B.175.244;2.B.240.228; 2.B.240.229; 2.B.240.230; 2.B.240.231; 2.B.240.236;2.B.240.237; 2.B.240.238; 2.B.240.239; 2.B.240.154; 2.B.240.157;2.B.240.166; 2.B.240.169; 2.B.240.172; 2.B.240.175; 2.B.240.240;2.B.240.244; 2.B.244.228; 2.B.244.229; 2.B.244.230; 2.B.244.231;2.B.244.236; 2.B.244.237; 2.B.244.238; 2.B.244.239; 2.B.244.154;2.B.244.157; 2.B.244.166; 2.B.244.169; 2.B.244.172; 2.B.244.175;2.B.244.240; 2.B.244.244; Prodrugs of 2.D 2.D.228.228; 2.D.228.229;2.D.228.230; 2.D.228.231; 2.D.228.236; 2.D.228.237; 2.D.228.238;2.D.228.239; 2.D.228.154; 2.D.228.157; 2.D.228.166; 2.D.228.169;2.D.228.172; 2.D.228.175; 2.D.228.240; 2.D.228.244; 2.D.229.228;2.D.229.229; 2.D.229.230; 2.D.229.231; 2.D.229.236; 2.D.229.237;2.D.229.238; 2.D.229.239; 2.D.229.154; 2.D.229.157; 2.D.229.166;2.D.229.169; 2.D.229.172; 2.D.229.175; 2.D.229.240; 2.D.229.244;2.D.230.228; 2.D.230.229; 2.D.230.230; 2.D.230.231; 2.D.230.236;2.D.230.237; 2.D.230.238; 2.D.230.239; 2.D.230.154; 2.D.230.157;2.D.230.166; 2.D.230.169; 2.D.230.172; 2.D.230.175; 2.D.230.240;2.D.230.244; 2.D.231.228; 2.D.231.229; 2.D.231.230; 2.D.231.231;2.D.231.236; 2.D.231.237; 2.D.231.238; 2.D.231.239; 2.D.231.154;2.D.231.157; 2.D.231.166; 2.D.231.169; 2.D.231.172; 2.D.231.175;2.D.231.240; 2.D.231.244; 2.D.236.228; 2.D.236.229; 2.D.236.230;2.D.236.231; 2.D.236.236; 2.D.236.237; 2.D.236.238; 2.D.236.239;2.D.236.154; 2.D.236.157; 2.D.236.166; 2.D.236.169; 2.D.236.172;2.D.236.175; 2.D.236.240; 2.D.236.244; 2.D.237.228; 2.D.237.229;2.D.237.230; 2.D.237.231; 2.D.237.236; 2.D.237.237; 2.D.237.238;2.D.237.239; 2.D.237.154; 2.D.237.157; 2.D.237.166; 2.D.237.169;2.D.237.172; 2.D.237.175; 2.D.237.240; 2.D.237.244; 2.D.238.228;2.D.238.229; 2.D.238.230; 2.D.238.231; 2.D.238.236; 2.D.238.237;2.D.238.238; 2.D.238.239; 2.D.238.154; 2.D.238.157; 2.D.238.166;2.D.238.169; 2.D.238.172; 2.D.238.175; 2.D.238.240; 2.D.238.244;2.D.239.228; 2.D.239.229; 2.D.239.230; 2.D.239.231; 2.D.239.236;2.D.239.237; 2.D.239.238; 2.D.239.239; 2.D.239.154; 2.D.239.157;2.D.239.166; 2.D.239.169; 2.D.239.172; 2.D.239.175; 2.D.239.240;2.D.239.244; 2.D.154.228; 2.D.154.229; 2.D.154.230; 2.D.154.231;2.D.154.236; 2.D.154.237; 2.D.154.238; 2.D.154.239; 2.D.154.154;2.D.154.157; 2.D.154.166; 2.D.154.169; 2.D.154.172; 2.D.154.175;2.D.154.240; 2.D.154.244; 2.D.157.228; 2.D.157.229; 2.D.157.230;2.D.157.231; 2.D.157.236; 2.D.157.237; 2.D.157.238; 2.D.157.239;2.D.157.154; 2.D.157.157; 2.D.157.166; 2.D.157.169; 2.D.157.172;2.D.157.175; 2.D.157.240; 2.D.157.244; 2.D.166.228; 2.D.166.229;2.D.166.230; 2.D.166.231; 2.D.166.236; 2.D.166.237; 2.D.166.238;2.D.166.239; 2.D.166.154; 2.D.166.157; 2.D.166.166; 2.D.166.169;2.D.166.172; 2.D.166.175; 2.D.166.240; 2.D.166.244; 2.D.169.228;2.D.169.229; 2.D.169.230; 2.D.169.231; 2.D.169.236; 2.D.169.237;2.D.169.238; 2.D.169.239; 2.D.169.154; 2.D.169.157; 2.D.169.166;2.D.169.169; 2.D.169.172; 2.D.169.175; 2.D.169.240; 2.D.169.244;2.D.172.228; 2.D.172.229; 2.D.172.230; 2.D.172.231; 2.D.172.236;2.D.172.237; 2.D.172.238; 2.D.172.239; 2.D.172.154; 2.D.172.157;2.D.172.166; 2.D.172.169; 2.D.172.172; 2.D.172.175; 2.D.172.240;2.D.172.244; 2.D.175.228; 2.D.175.229; 2.D.175.230; 2.D.175.231;2.D.175.236; 2.D.175.237; 2.D.175.238; 2.D.175.239; 2.D.175.154;2.D.175.157; 2.D.175.166; 2.D.175.169; 2.D.175.172; 2.D.175.175;2.D.175.240; 2.D.175.244; 2.D.240.228; 2.D.240.229; 2.D.240.230;2.D.240.231; 2.D.240.236; 2.D.240.237; 2.D.240.238; 2.D.240.239;2.D.240.154; 2.D.240.157; 2.D.240.166; 2.D.240.169; 2.D.240.172;2.D.240.175; 2.D.240.240; 2.D.240.244; 2.D.244.228; 2.D.244.229;2.D.244.230; 2.D.244.231; 2.D.244.236; 2.D.244.237; 2.D.244.238;2.D.244.239; 2.D.244.154; 2.D.244.157; 2.D.244.166; 2.D.244.169;2.D.244.172; 2.D.244.175; 2.D.244.240; 2.D.244.244; Prodrugs of 2.E2.E.228.228; 2.E.228.229; 2.E.228.230; 2.E.228.231; 2.E.228.236;2.E.228.237; 2.E.228.238; 2.E.228.239; 2.E.228.154; 2.E.228.157;2.E.228.166; 2.E.228.169; 2.E.228.172; 2.E.228.175; 2.E.228.240;2.E.228.244; 2.E.229.228; 2.E.229.229; 2.E.229.230; 2.E.229.231;2.E.229.236; 2.E.229.237; 2.E.229.238; 2.E.229.239; 2.E.229.154;2.E.229.157; 2.E.229.166; 2.E.229.169; 2.E.229.172; 2.E.229.175;2.E.229.240; 2.E.229.244; 2.E.230.228; 2.E.230.229; 2.E.230.230;2.E.230.231; 2.E.230.236; 2.E.230.237; 2.E.230.238; 2.E.230.239;2.E.230.154; 2.E.230.157; 2.E.230.166; 2.E.230.169; 2.E.230.172;2.E.230.175; 2.E.230.240; 2.E.230.244; 2.E.231.228; 2.E.231.229;2.E.231.230; 2.E.231.231; 2.E.231.236; 2.E.231.237; 2.E.231.238;2.E.231.239; 2.E.231.154; 2.E.231.157; 2.E.231.166; 2.E.231.169;2.E.231.172; 2.E.231.175; 2.E.231.240; 2.E.231.244; 2.E.236.228;2.E.236.229; 2.E.236.230; 2.E.236.231; 2.E.236.236; 2.E.236.237;2.E.236.238; 2.E.236.239; 2.E.236.154; 2.E.236.157; 2.E.236.166;2.E.236.169; 2.E.236.172; 2.E.236.175; 2.E.236.240; 2.E.236.244;2.E.237.228; 2.E.237.229; 2.E.237.230; 2.E.237.231; 2.E.237.236;2.E.237.237; 2.E.237.238; 2.E.237.239; 2.E.237.154; 2.E.237.157;2.E.237.166; 2.E.237.169; 2.E.237.172; 2.E.237.175; 2.E.237.240;2.E.237.244; 2.E.238.228; 2.E.238.229; 2.E.238.230; 2.E.238.231;2.E.238.236; 2.E.238.237; 2.E.238.238; 2.E.238.239; 2.E.238.154;2.E.238.157; 2.E.238.166; 2.E.238.169; 2.E.238.172; 2.E.238.175;2.E.238.240; 2.E.238.244; 2.E.239.228; 2.E.239.229; 2.E.239.230;2.E.239.231; 2.E.239.236; 2.E.239.237; 2.E.239.238; 2.E.239.239;2.E.239.154; 2.E.239.157; 2.E.239.166; 2.E.239.169; 2.E.239.172;2.E.239.175; 2.E.239.240; 2.E.239.244; 2.E.154.228; 2.E.154.229;2.E.154.230; 2.E.154.231; 2.E.154.236; 2.E.154.237; 2.E.154.238;2.E.154.239; 2.E.154.154; 2.E.154.157; 2.E.154.166; 2.E.154.169;2.E.154.172; 2.E.154.175; 2.E.154.240; 2.E.154.244; 2.E.157.228;2.E.157.229; 2.E.157.230; 2.E.157.231; 2.E.157.236; 2.E.157.237;2.E.157.238; 2.E.157.239; 2.E.157.154; 2.E.157.157; 2.E.157.166;2.E.157.169; 2.E.157.172; 2.E.157.175; 2.E.157.240; 2.E.157.244;2.E.166.228; 2.E.166.229; 2.E.166.230; 2.E.166.231; 2.E.166.236;2.E.166.237; 2.E.166.238; 2.E.166.239; 2.E.166.154; 2.E.166.157;2.E.166.166; 2.E.166.169; 2.E.166.172; 2.E.166.175; 2.E.166.240;2.E.166.244; 2.E.169.228; 2.E.169.229; 2.E.169.230; 2.E.169.231;2.E.169.236; 2.E.169.237; 2.E.169.238; 2.E.169.239; 2.E.169.154;2.E.169.157; 2.E.169.166; 2.E.169.169; 2.E.169.172; 2.E.169.175;2.E.169.240; 2.E.169.244; 2.E.172.228; 2.E.172.229; 2.E.172.230;2.E.172.231; 2.E.172.236; 2.E.172.237; 2.E.172.238; 2.E.172.239;2.E.172.154; 2.E.172.157; 2.E.172.166; 2.E.172.169; 2.E.172.172;2.E.172.175; 2.E.172.240; 2.E.172.244; 2.E.175.228; 2.E.175.229;2.E.175.230; 2.E.175.231; 2.E.175.236; 2.E.175.237; 2.E.175.238;2.E.175.239; 2.E.175.154; 2.E.175.157; 2.E.175.166; 2.E.175.169;2.E.175.172; 2.E.175.175; 2.E.175.240; 2.E.175.244; 2.E.240.228;2.E.240.229; 2.E.240.230; 2.E.240.231; 2.E.240.236; 2.E.240.237;2.E.240.238; 2.E.240.239; 2.E.240.154; 2.E.240.157; 2.E.240.166;2.E.240.169; 2.E.240.172; 2.E.240.175; 2.E.240.240; 2.E.240.244;2.E.244.228; 2.E.244.229; 2.E.244.230; 2.E.244.231; 2.E.244.236;2.E.244.237; 2.E.244.238; 2.E.244.239; 2.E.244.154; 2.E.244.157;2.E.244.166; 2.E.244.169; 2.E.244.172; 2.E.244.175; 2.E.244.240;2.E.244.244; Prodrugs of 2.G 2.G.228.228; 2.G.228.229; 2.G.228.230;2.G.228.231; 2.G.228.236; 2.G.228.237; 2.G.228.238; 2.G.228.239;2.G.228.154; 2.G.228.157; 2.G.228.166; 2.G.228.169; 2.G.228.172;2.G.228.175; 2.G.228.240; 2.G.228.244; 2.G.229.228; 2.G.229.229;2.G.229.230; 2.G.229.231; 2.G.229.236; 2.G.229.237; 2.G.229.238;2.G.229.239; 2.G.229.154; 2.G.229.157; 2.G.229.166; 2.G.229.169;2.G.229.172; 2.G.229.175; 2.G.229.240; 2.G.229.244; 2.G.230.228;2.G.230.229; 2.G.230.230; 2.G.230.231; 2.G.230.236; 2.G.230.237;2.G.230.238; 2.G.230.239; 2.G.230.154; 2.G.230.157; 2.G.230.166;2.G.230.169; 2.G.230.172; 2.G.230.175; 2.G.230.240; 2.G.230.244;2.G.231.228; 2.G.231.229; 2.G.231.230; 2.G.231.231; 2.G.231.236;2.G.231.237; 2.G.231.238; 2.G.231.239; 2.G.231.154; 2.G.231.157;2.G.231.166; 2.G.231.169; 2.G.231.172; 2.G.231.175; 2.G.231.240;2.G.231.244; 2.G.236.228; 2.G.236.229; 2.G.236.230; 2.G.236.231;2.G.236.236; 2.G.236.237; 2.G.236.238; 2.G.236.239; 2.G.236.154;2.G.236.157; 2.G.236.166; 2.G.236.169; 2.G.236.172; 2.G.236.175;2.G.236.240; 2.G.236.244; 2.G.237.228; 2.G.237.229; 2.G.237.230;2.G.237.231; 2.G.237.236; 2.G.237.237; 2.G.237.238; 2.G.237.239;2.G.237.154; 2.G.237.157; 2.G.237.166; 2.G.237.169; 2.G.237.172;2.G.237.175; 2.G.237.240; 2.G.237.244; 2.G.238.228; 2.G.238.229;2.G.238.230; 2.G.238.231; 2.G.238.236; 2.G.238.237; 2.G.238.238;2.G.238.239; 2.G.238.154; 2.G.238.157; 2.G.238.166; 2.G.238.169;2.G.238.172; 2.G.238.175; 2.G.238.240; 2.G.238.244; 2.G.239.228;2.G.239.229; 2.G.239.230; 2.G.239.231; 2.G.239.236; 2.G.239.237;2.G.239.238; 2.G.239.239; 2.G.239.154; 2.G.239.157; 2.G.239.166;2.G.239.169; 2.G.239.172; 2.G.239.175; 2.G.239.240; 2.G.239.244;2.G.154.228; 2.G.154.229; 2.G.154.230; 2.G.154.231; 2.G.154.236;2.G.154.237; 2.G.154.238; 2.G.154.239; 2.G.154.154; 2.G.154.157;2.G.154.166; 2.G.154.169; 2.G.154.172; 2.G.154.175; 2.G.154.240;2.G.154.244; 2.G.157.228; 2.G.157.229; 2.G.157.230; 2.G.157.231;2.G.157.236; 2.G.157.237; 2.G.157.238; 2.G.157.239; 2.G.157.154;2.G.157.157; 2.G.157.166; 2.G.157.169; 2.G.157.172; 2.G.157.175;2.G.157.240; 2.G.157.244; 2.G.166.228; 2.G.166.229; 2.G.166.230;2.G.166.231; 2.G.166.236; 2.G.166.237; 2.G.166.238; 2.G.166.239;2.G.166.154; 2.G.166.157; 2.G.166.166; 2.G.166.169; 2.G.166.172;2.G.166.175; 2.G.166.240; 2.G.166.244; 2.G.169.228; 2.G.169.229;2.G.169.230; 2.G.169.231; 2.G.169.236; 2.G.169.237; 2.G.169.238;2.G.169.239; 2.G.169.154; 2.G.169.157; 2.G.169.166; 2.G.169.169;2.G.169.172; 2.G.169.175; 2.G.169.240; 2.G.169.244; 2.G.172.228;2.G.172.229; 2.G.172.230; 2.G.172.231; 2.G.172.236; 2.G.172.237;2.G.172.238; 2.G.172.239; 2.G.172.154; 2.G.172.157; 2.G.172.166;2.G.172.169; 2.G.172.172; 2.G.172.175; 2.G.172.240; 2.G.172.244;2.G.175.228; 2.G.175.229; 2.G.175.230; 2.G.175.231; 2.G.175.236;2.G.175.237; 2.G.175.238; 2.G.175.239; 2.G.175.154; 2.G.175.157;2.G.175.166; 2.G.175.169; 2.G.175.172; 2.G.175.175; 2.G.175.240;2.G.175.244; 2.G.240.228; 2.G.240.229; 2.G.240.230; 2.G.240.231;2.G.240.236; 2.G.240.237; 2.G.240.238; 2.G.240.239; 2.G.240.154;2.G.240.157; 2.G.240.166; 2.G.240.169; 2.G.240.172; 2.G.240.175;2.G.240.240; 2.G.240.244; 2.G.244.228; 2.G.244.229; 2.G.244.230;2.G.244.231; 2.G.244.236; 2.G.244.237; 2.G.244.238; 2.G.244.239;2.G.244.154; 2.G.244.157; 2.G.244.166; 2.G.244.169; 2.G.244.172;2.G.244.175; 2.G.244.240; 2.G.244.244; Prodrugs of 2.I 2.I.228.228;2.I.228.229; 2.I.228.230; 2.I.228.231; 2.I.228.236; 2.I.228.237;2.I.228.238; 2.I.228.239; 2.I.228.154; 2.I.228.157; 2.I.228.166;2.I.228.169; 2.I.228.172; 2.I.228.175; 2.I.228.240; 2.I.228.244;2.I.229.228; 2.I.229.229; 2.I.229.230; 2.I.229.231; 2.I.229.236;2.I.229.237; 2.I.229.238; 2.I.229.239; 2.I.229.154; 2.I.229.157;2.I.229.166; 2.I.229.169; 2.I.229.172; 2.I.229.175; 2.I.229.240;2.I.229.244; 2.I.230.228; 2.I.230.229; 2.I.230.230; 2.I.230.231;2.I.230.236; 2.I.230.237; 2.I.230.238; 2.I.230.239; 2.I.230.154;2.I.230.157; 2.I.230.166; 2.I.230.169; 2.I.230.172; 2.I.230.175;2.I.230.240; 2.I.230.244; 2.I.231.228; 2.I.231.229; 2.I.231.230;2.I.231.231; 2.I.231.236; 2.I.231.237; 2.I.231.238; 2.I.231.239;2.I.231.154; 2.I.231.157; 2.I.231.166; 2.I.231.169; 2.I.231.172;2.I.231.175; 2.I.231.240; 2.I.231.244; 2.I.236.228; 2.I.236.229;2.I.236.230; 2.I.236.231; 2.I.236.236; 2.I.236.237; 2.I.236.238;2.I.236.239; 2.I.236.154; 2.I.236.157; 2.I.236.166; 2.I.236.169;2.I.236.172; 2.I.236.175; 2.I.236.240; 2.I.236.244; 2.I.237.228;2.I.237.229; 2.I.237.230; 2.I.237.231; 2.I.237.236; 2.I.237.237;2.I.237.238; 2.I.237.239; 2.I.237.154; 2.I.237.157; 2.I.237.166;2.I.237.169; 2.I.237.172; 2.I.237.175; 2.I.237.240; 2.I.237.244;2.I.238.228; 2.I.238.229; 2.I.238.230; 2.I.238.231; 2.I.238.236;2.I.238.237; 2.I.238.238; 2.I.238.239; 2.I.238.154; 2.I.238.157;2.I.238.166; 2.I.238.169; 2.I.238.172; 2.I.238.175; 2.I.238.240;2.I.238.244; 2.I.239.228; 2.I.239.229; 2.I.239.230; 2.I.239.231;2.I.239.236; 2.I.239.237; 2.I.239.238; 2.I.239.239; 2.I.239.154;2.I.239.157; 2.I.239.166; 2.I.239.169; 2.I.239.172; 2.I.239.175;2.I.239.240; 2.I.239.244; 2.I.154.228; 2.I.154.229; 2.I.154.230;2.I.154.231; 2.I.154.236; 2.I.154.237; 2.I.154.238; 2.I.154.239;2.I.154.154; 2.I.154.157; 2.I.154.166; 2.I.154.169; 2.I.154.172;2.I.154.175; 2.I.154.240; 2.I.154.244; 2.I.157.228; 2.I.157.229;2.I.157.230; 2.I.157.231; 2.I.157.236; 2.I.157.237; 2.I.157.238;2.I.157.239; 2.I.157.154; 2.I.157.157; 2.I.157.166; 2.I.157.169;2.I.157.172; 2.I.157.175; 2.I.157.240; 2.I.157.244; 2.I.166.228;2.I.166.229; 2.I.166.230; 2.I.166.231; 2.I.166.236; 2.I.166.237;2.I.166.238; 2.I.166.239; 2.I.166.154; 2.I.166.157; 2.I.166.166;2.I.166.169; 2.I.166.172; 2.I.166.175; 2.I.166.240; 2.I.166.244;2.I.169.228; 2.I.169.229; 2.I.169.230; 2.I.169.231; 2.I.169.236;2.I.169.237; 2.I.169.238; 2.I.169.239; 2.I.169.154; 2.I.169.157;2.I.169.166; 2.I.169.169; 2.I.169.172; 2.I.169.175; 2.I.169.240;2.I.169.244; 2.I.172.228; 2.I.172.229; 2.I.172.230; 2.I.172.231;2.I.172.236; 2.I.172.237; 2.I.172.238; 2.I.172.239; 2.I.172.154;2.I.172.157; 2.I.172.166; 2.I.172.169; 2.I.172.172; 2.I.172.175;2.I.172.240; 2.I.172.244; 2.I.175.228; 2.I.175.229; 2.I.175.230;2.I.175.231; 2.I.175.236; 2.I.175.237; 2.I.175.238; 2.I.175.239;2.I.175.154; 2.I.175.157; 2.I.175.166; 2.I.175.169; 2.I.175.172;2.I.175.175; 2.I.175.240; 2.I.175.244; 2.I.240.228; 2.I.240.229;2.I.240.230; 2.I.240.231; 2.I.240.236; 2.I.240.237; 2.I.240.238;2.I.240.239; 2.I.240.154; 2.I.240.157; 2.I.240.166; 2.I.240.169;2.I.240.172; 2.I.240.175; 2.I.240.240; 2.I.240.244; 2.I.244.228;2.I.244.229; 2.I.244.230; 2.I.244.231; 2.I.244.236; 2.I.244.237;2.I.244.238; 2.I.244.239; 2.I.244.154; 2.I.244.157; 2.I.244.166;2.I.244.169; 2.I.244.172; 2.I.244.175; 2.I.244.240; 2.I.244.244;Prodrugs of 2.J 2.J.228.228; 2.J.228.229; 2.J.228.230; 2.J.228.231;2.J.228.236; 2.J.228.237; 2.J.228.238; 2.J.228.239; 2.J.228.154;2.J.228.157; 2.J.228.166; 2.J.228.169; 2.J.228.172; 2.J.228.175;2.J.228.240; 2.J.228.244; 2.J.229.228; 2.J.229.229; 2.J.229.230;2.J.229.231; 2.J.229.236; 2.J.229.237; 2.J.229.238; 2.J.229.239;2.J.229.154; 2.J.229.157; 2.J.229.166; 2.J.229.169; 2.J.229.172;2.J.229.175; 2.J.229.240; 2.J.229.244; 2.J.230.228; 2.J.230.229;2.J.230.230; 2.J.230.231; 2.J.230.236; 2.J.230.237; 2.J.230.238;2.J.230.239; 2.J.230.154; 2.J.230.157; 2.J.230.166; 2.J.230.169;2.J.230.172; 2.J.230.175; 2.J.230.240; 2.J.230.244; 2.J.231.228;2.J.231.229; 2.J.231.230; 2.J.231.231; 2.J.231.236; 2.J.231.237;2.J.231.238; 2.J.231.239; 2.J.231.154; 2.J.231.157; 2.J.231.166;2.J.231.169; 2.J.231.172; 2.J.231.175; 2.J.231.240; 2.J.231.244;2.J.236.228; 2.J.236.229; 2.J.236.230; 2.J.236.231; 2.J.236.236;2.J.236.237; 2.J.236.238; 2.J.236.239; 2.J.236.154; 2.J.236.157;2.J.236.166; 2.J.236.169; 2.J.236.172; 2.J.236.175; 2.J.236.240;2.J.236.244; 2.J.237.228; 2.J.237.229; 2.J.237.230; 2.J.237.231;2.J.237.236; 2.J.237.237; 2.J.237.238; 2.J.237.239; 2.J.237.154;2.J.237.157; 2.J.237.166; 2.J.237.169; 2.J.237.172; 2.J.237.175;2.J.237.240; 2.J.237.244; 2.J.238.228; 2.J.238.229; 2.J.238.230;2.J.238.231; 2.J.238.236; 2.J.238.237; 2.J.238.238; 2.J.238.239;2.J.238.154; 2.J.238.157; 2.J.238.166; 2.J.238.169; 2.J.238.172;2.J.238.175; 2.J.238.240; 2.J.238.244; 2.J.239.228; 2.J.239.229;2.J.239.230; 2.J.239.231; 2.J.239.236; 2.J.239.237; 2.J.239.238;2.J.239.239; 2.J.239.154; 2.J.239.157; 2.J.239.166; 2.J.239.169;2.J.239.172; 2.J.239.175; 2.J.239.240; 2.J.239.244; 2.J.154.228;2.J.154.229; 2.J.154.230; 2.J.154.231; 2.J.154.236; 2.J.154.237;2.J.154.238; 2.J.154.239; 2.J.154.154; 2.J.154.157; 2.J.154.166;2.J.154.169; 2.J.154.172; 2.J.154.175; 2.J.154.240; 2.J.154.244;2.J.157.228; 2.J.157.229; 2.J.157.230; 2.J.157.231; 2.J.157.236;2.J.157.237; 2.J.157.238; 2.J.157.239; 2.J.157.154; 2.J.157.157;2.J.157.166; 2.J.157.169; 2.J.157.172; 2.J.157.175; 2.J.157.240;2.J.157.244; 2.J.166.228; 2.J.166.229; 2.J.166.230; 2.J.166.231;2.J.166.236; 2.J.166.237; 2.J.166.238; 2.J.166.239; 2.J.166.154;2.J.166.157; 2.J.166.166; 2.J.166.169; 2.J.166.172; 2.J.166.175;2.J.166.240; 2.J.166.244; 2.J.169.228; 2.J.169.229; 2.J.169.230;2.J.169.231; 2.J.169.236; 2.J.169.237; 2.J.169.238; 2.J.169.239;2.J.169.154; 2.J.169.157; 2.J.169.166; 2.J.169.169; 2.J.169.172;2.J.169.175; 2.J.169.240; 2.J.169.244; 2.J.172.228; 2.J.172.229;2.J.172.230; 2.J.172.231; 2.J.172.236; 2.J.172.237; 2.J.172.238;2.J.172.239; 2.J.172.154; 2.J.172.157; 2.J.172.166; 2.J.172.169;2.J.172.172; 2.J.172.175; 2.J.172.240; 2.J.172.244; 2.J.175.228;2.J.175.229; 2.J.175.230; 2.J.175.231; 2.J.175.236; 2.J.175.237;2.J.175.238; 2.J.175.239; 2.J.175.154; 2.J.175.157; 2.J.175.166;2.J.175.169; 2.J.175.172; 2.J.175.175; 2.J.175.240; 2.J.175.244;2.J.240.228; 2.J.240.229; 2.J.240.230; 2.J.240.231; 2.J.240.236;2.J.240.237; 2.J.240.238; 2.J.240.239; 2.J.240.154; 2.J.240.157;2.J.240.166; 2.J.240.169; 2.J.240.172; 2.J.240.175; 2.J.240.240;2.J.240.244; 2.J.244.228; 2.J.244.229; 2.J.244.230; 2.J.244.231;2.J.244.236; 2.J.244.237; 2.J.244.238; 2.J.244.239; 2.J.244.154;2.J.244.157; 2.J.244.166; 2.J.244.169; 2.J.244.172; 2.J.244.175;2.J.244.240; 2.J.244.244; Prodrugs of 2.L 2.L.228.228; 2.L.228.229;2.L.228.230; 2.L.228.231; 2.L.228.236; 2.L.228.237; 2.L.228.238;2.L.228.239; 2.L.228.154; 2.L.228.157; 2.L.228.166; 2.L.228.169;2.L.228.172; 2.L.228.175; 2.L.228.240; 2.L.228.244; 2.L.229.228;2.L.229.229; 2.L.229.230; 2.L.229.231; 2.L.229.236; 2.L.229.237;2.L.229.238; 2.L.229.239; 2.L.229.154; 2.L.229.157; 2.L.229.166;2.L.229.169; 2.L.229.172; 2.L.229.175; 2.L.229.240; 2.L.229.244;2.L.230.228; 2.L.230.229; 2.L.230.230; 2.L.230.231; 2.L.230.236;2.L.230.237; 2.L.230.238; 2.L.230.239; 2.L.230.154; 2.L.230.157;2.L.230.166; 2.L.230.169; 2.L.230.172; 2.L.230.175; 2.L.230.240;2.L.230.244; 2.L.231.228; 2.L.231.229; 2.L.231.230; 2.L.231.231;2.L.231.236; 2.L.231.237; 2.L.231.238; 2.L.231.239; 2.L.231.154;2.L.231.157; 2.L.231.166; 2.L.231.169; 2.L.231.172; 2.L.231.175;2.L.231.240; 2.L.231.244; 2.L.236.228; 2.L.236.229; 2.L.236.230;2.L.236.231; 2.L.236.236; 2.L.236.237; 2.L.236.238; 2.L.236.239;2.L.236.154; 2.L.236.157; 2.L.236.166; 2.L.236.169; 2.L.236.172;2.L.236.175; 2.L.236.240; 2.L.236.244; 2.L.237.228; 2.L.237.229;2.L.237.230; 2.L.237.231; 2.L.237.236; 2.L.237.237; 2.L.237.238;2.L.237.239; 2.L.237.154; 2.L.237.157; 2.L.237.166; 2.L.237.169;2.L.237.172; 2.L.237.175; 2.L.237.240; 2.L.237.244; 2.L.238.228;2.L.238.229; 2.L.238.230; 2.L.238.231; 2.L.238.236; 2.L.238.237;2.L.238.238; 2.L.238.239; 2.L.238.154; 2.L.238.157; 2.L.238.166;2.L.238.169; 2.L.238.172; 2.L.238.175; 2.L.238.240; 2.L.238.244;2.L.239.228; 2.L.239.229; 2.L.239.230; 2.L.239.231; 2.L.239.236;2.L.239.237; 2.L.239.238; 2.L.239.239; 2.L.239.154; 2.L.239.157;2.L.239.166; 2.L.239.169; 2.L.239.172; 2.L.239.175; 2.L.239.240;2.L.239.244; 2.L.154.228; 2.L.154.229; 2.L.154.230; 2.L.154.231;2.L.154.236; 2.L.154.237; 2.L.154.238; 2.L.154.239; 2.L.154.154;2.L.154.157; 2.L.154.166; 2.L.154.169; 2.L.154.172; 2.L.154.175;2.L.154.240; 2.L.154.244; 2.L.157.228; 2.L.157.229; 2.L.157.230;2.L.157.231; 2.L.157.236; 2.L.157.237; 2.L.157.238; 2.L.157.239;2.L.157.154; 2.L.157.157; 2.L.157.166; 2.L.157.169; 2.L.157.172;2.L.157.175; 2.L.157.240; 2.L.157.244; 2.L.166.228; 2.L.166.229;2.L.166.230; 2.L.166.231; 2.L.166.236; 2.L.166.237; 2.L.166.238;2.L.166.239; 2.L.166.154; 2.L.166.157; 2.L.166.166; 2.L.166.169;2.L.166.172; 2.L.166.175; 2.L.166.240; 2.L.166.244; 2.L.169.228;2.L.169.229; 2.L.169.230; 2.L.169.231; 2.L.169.236; 2.L.169.237;2.L.169.238; 2.L.169.239; 2.L.169.154; 2.L.169.157; 2.L.169.166;2.L.169.169; 2.L.169.172; 2.L.169.175; 2.L.169.240; 2.L.169.244;2.L.172.228; 2.L.172.229; 2.L.172.230; 2.L.172.231; 2.L.172.236;2.L.172.237; 2.L.172.238; 2.L.172.239; 2.L.172.154; 2.L.172.157;2.L.172.166; 2.L.172.169; 2.L.172.172; 2.L.172.175; 2.L.172.240;2.L.172.244; 2.L.175.228; 2.L.175.229; 2.L.175.230; 2.L.175.231;2.L.175.236; 2.L.175.237; 2.L.175.238; 2.L.175.239; 2.L.175.154;2.L.175.157; 2.L.175.166; 2.L.175.169; 2.L.175.172; 2.L.175.175;2.L.175.240; 2.L.175.244; 2.L.240.228; 2.L.240.229; 2.L.240.230;2.L.240.231; 2.L.240.236; 2.L.240.237; 2.L.240.238; 2.L.240.239;2.L.240.154; 2.L.240.157; 2.L.240.166; 2.L.240.169; 2.L.240.172;2.L.240.175; 2.L.240.240; 2.L.240.244; 2.L.244.228; 2.L.244.229;2.L.244.230; 2.L.244.231; 2.L.244.236; 2.L.244.237; 2.L.244.238;2.L.244.239; 2.L.244.154; 2.L.244.157; 2.L.244.166; 2.L.244.169;2.L.244.172; 2.L.244.175; 2.L.244.240; 2.L.244.244; Prodrugs of 2.O2.O.228.228; 2.O.228.229; 2.O.228.230; 2.O.228.231; 2.O.228.236;2.O.228.237; 2.O.228.238; 2.O.228.239; 2.O.228.154; 2.O.228.157;2.O.228.166; 2.O.228.169; 2.O.228.172; 2.O.228.175; 2.O.228.240;2.O.228.244; 2.O.229.228; 2.O.229.229; 2.O.229.230; 2.O.229.231;2.O.229.236; 2.O.229.237; 2.O.229.238; 2.O.229.239; 2.O.229.154;2.O.229.157; 2.O.229.166; 2.O.229.169; 2.O.229.172; 2.O.229.175;2.O.229.240; 2.O.229.244; 2.O.230.228; 2.O.230.229; 2.O.230.230;2.O.230.231; 2.O.230.236; 2.O.230.237; 2.O.230.238; 2.O.230.239;2.O.230.154; 2.O.230.157; 2.O.230.166; 2.O.230.169; 2.O.230.172;2.O.230.175; 2.O.230.240; 2.O.230.244; 2.O.231.228; 2.O.231.229;2.O.231.230; 2.O.231.231; 2.O.231.236; 2.O.231.237; 2.O.231.238;2.O.231.239; 2.O.231.154; 2.O.231.157; 2.O.231.166; 2.O.231.169;2.O.231.172; 2.O.231.175; 2.O.231.240; 2.O.231.244; 2.O.236.228;2.O.236.229; 2.O.236.230; 2.O.236.231; 2.O.236.236; 2.O.236.237;2.O.236.238; 2.O.236.239; 2.O.236.154; 2.O.236.157; 2.O.236.166;2.O.236.169; 2.O.236.172; 2.O.236.175; 2.O.236.240; 2.O.236.244;2.O.237.228; 2.O.237.229; 2.O.237.230; 2.O.237.231; 2.O.237.236;2.O.237.237; 2.O.237.238; 2.O.237.239; 2.O.237.154; 2.O.237.157;2.O.237.166; 2.O.237.169; 2.O.237.172; 2.O.237.175; 2.O.237.240;2.O.237.244; 2.O.238.228; 2.O.238.229; 2.O.238.230; 2.O.238.231;2.O.238.236; 2.O.238.237; 2.O.238.238; 2.O.238.239; 2.O.238.154;2.O.238.157; 2.O.238.166; 2.O.238.169; 2.O.238.172; 2.O.238.175;2.O.238.240; 2.O.238.244; 2.O.239.228; 2.O.239.229; 2.O.239.230;2.O.239.231; 2.O.239.236; 2.O.239.237; 2.O.239.238; 2.O.239.239;2.O.239.154; 2.O.239.157; 2.O.239.166; 2.O.239.169; 2.O.239.172;2.O.239.175; 2.O.239.240; 2.O.239.244; 2.O.154.228; 2.O.154.229;2.O.154.230; 2.O.154.231; 2.O.154.236; 2.O.154.237; 2.O.154.238;2.O.154.239; 2.O.154.154; 2.O.154.157; 2.O.154.166; 2.O.154.169;2.O.154.172; 2.O.154.175; 2.O.154.240; 2.O.154.244; 2.O.157.228;2.O.157.229; 2.O.157.230; 2.O.157.231; 2.O.157.236; 2.O.157.237;2.O.157.238; 2.O.157.239; 2.O.157.154; 2.O.157.157; 2.O.157.166;2.O.157.169; 2.O.157.172; 2.O.157.175; 2.O.157.240; 2.O.157.244;2.O.166.228; 2.O.166.229; 2.O.166.230; 2.O.166.231; 2.O.166.236;2.O.166.237; 2.O.166.238; 2.O.166.239; 2.O.166.154; 2.O.166.157;2.O.166.166; 2.O.166.169; 2.O.166.172; 2.O.166.175; 2.O.166.240;2.O.166.244; 2.O.169.228; 2.O.169.229; 2.O.169.230; 2.O.169.231;2.O.169.236; 2.O.169.237; 2.O.169.238; 2.O.169.239; 2.O.169.154;2.O.169.157; 2.O.169.166; 2.O.169.169; 2.O.169.172; 2.O.169.175;2.O.169.240; 2.O.169.244; 2.O.172.228; 2.O.172.229; 2.O.172.230;2.O.172.231; 2.O.172.236; 2.O.172.237; 2.O.172.238; 2.O.172.239;2.O.172.154; 2.O.172.157; 2.O.172.166; 2.O.172.169; 2.O.172.172;2.O.172.175; 2.O.172.240; 2.O.172.244; 2.O.175.228; 2.O.175.229;2.O.175.230; 2.O.175.231; 2.O.175.236; 2.O.175.237; 2.O.175.238;2.O.175.239; 2.O.175.154; 2.O.175.157; 2.O.175.166; 2.O.175.169;2.O.175.172; 2.O.175.175; 2.O.175.240; 2.O.175.244; 2.O.240.228;2.O.240.229; 2.O.240.230; 2.O.240.231; 2.O.240.236; 2.O.240.237;2.O.240.238; 2.O.240.239; 2.O.240.154; 2.O.240.157; 2.O.240.166;2.O.240.169; 2.O.240.172; 2.O.240.175; 2.O.240.240; 2.O.240.244;2.O.244.228; 2.O.244.229; 2.O.244.230; 2.O.244.231; 2.O.244.236;2.O.244.237; 2.O.244.238; 2.O.244.239; 2.O.244.154; 2.O.244.157;2.O.244.166; 2.O.244.169; 2.O.244.172; 2.O.244.175; 2.O.244.240;2.O.244.244; Prodrugs of 2.P 2.P.228.228; 2.P.228.229; 2.P.228.230;2.P.228.231; 2.P.228.236; 2.P.228.237; 2.P.228.238; 2.P.228.239;2.P.228.154; 2.P.228.157; 2.P.228.166; 2.P.228.169; 2.P.228.172;2.P.228.175; 2.P.228.240; 2.P.228.244; 2.P.229.228; 2.P.229.229;2.P.229.230; 2.P.229.231; 2.P.229.236; 2.P.229.237; 2.P.229.238;2.P.229.239; 2.P.229.154; 2.P.229.157; 2.P.229.166; 2.P.229.169;2.P.229.172; 2.P.229.175; 2.P.229.240; 2.P.229.244; 2.P.230.228;2.P.230.229; 2.P.230.230; 2.P.230.231; 2.P.230.236; 2.P.230.237;2.P.230.238; 2.P.230.239; 2.P.230.154; 2.P.230.157; 2.P.230.166;2.P.230.169; 2.P.230.172; 2.P.230.175; 2.P.230.240; 2.P.230.244;2.P.231.228; 2.P.231.229; 2.P.231.230; 2.P.231.231; 2.P.231.236;2.P.231.237; 2.P.231.238; 2.P.231.239; 2.P.231.154; 2.P.231.157;2.P.231.166; 2.P.231.169; 2.P.231.172; 2.P.231.175; 2.P.231.240;2.P.231.244; 2.P.236.228; 2.P.236.229; 2.P.236.230; 2.P.236.231;2.P.236.236; 2.P.236.237; 2.P.236.238; 2.P.236.239; 2.P.236.154;2.P.236.157; 2.P.236.166; 2.P.236.169; 2.P.236.172; 2.P.236.175;2.P.236.240; 2.P.236.244; 2.P.237.228; 2.P.237.229; 2.P.237.230;2.P.237.231; 2.P.237.236; 2.P.237.237; 2.P.237.238; 2.P.237.239;2.P.237.154; 2.P.237.157; 2.P.237.166; 2.P.237.169; 2.P.237.172;2.P.237.175; 2.P.237.240; 2.P.237.244; 2.P.238.228; 2.P.238.229;2.P.238.230; 2.P.238.231; 2.P.238.236; 2.P.238.237; 2.P.238.238;2.P.238.239; 2.P.238.154; 2.P.238.157; 2.P.238.166; 2.P.238.169;2.P.238.172; 2.P.238.175; 2.P.238.240; 2.P.238.244; 2.P.239.228;2.P.239.229; 2.P.239.230; 2.P.239.231; 2.P.239.236; 2.P.239.237;2.P.239.238; 2.P.239.239; 2.P.239.154; 2.P.239.157; 2.P.239.166;2.P.239.169; 2.P.239.172; 2.P.239.175; 2.P.239.240; 2.P.239.244;2.P.154.228; 2.P.154.229; 2.P.154.230; 2.P.154.231; 2.P.154.236;2.P.154.237; 2.P.154.238; 2.P.154.239; 2.P.154.154; 2.P.154.157;2.P.154.166; 2.P.154.169; 2.P.154.172; 2.P.154.175; 2.P.154.240;2.P.154.244; 2.P.157.228; 2.P.157.229; 2.P.157.230; 2.P.157.231;2.P.157.236; 2.P.157.237; 2.P.157.238; 2.P.157.239; 2.P.157.154;2.P.157.157; 2.P.157.166; 2.P.157.169; 2.P.157.172; 2.P.157.175;2.P.157.240; 2.P.157.244; 2.P.166.228; 2.P.166.229; 2.P.166.230;2.P.166.231; 2.P.166.236; 2.P.166.237; 2.P.166.238; 2.P.166.239;2.P.166.154; 2.P.166.157; 2.P.166.166; 2.P.166.169; 2.P.166.172;2.P.166.175; 2.P.166.240; 2.P.166.244; 2.P.169.228; 2.P.169.229;2.P.169.230; 2.P.169.231; 2.P.169.236; 2.P.169.237; 2.P.169.238;2.P.169.239; 2.P.169.154; 2.P.169.157; 2.P.169.166; 2.P.169.169;2.P.169.172; 2.P.169.175; 2.P.169.240; 2.P.169.244; 2.P.172.228;2.P.172.229; 2.P.172.230; 2.P.172.231; 2.P.172.236; 2.P.172.237;2.P.172.238; 2.P.172.239; 2.P.172.154; 2.P.172.157; 2.P.172.166;2.P.172.169; 2.P.172.172; 2.P.172.175; 2.P.172.240; 2.P.172.244;2.P.175.228; 2.P.175.229; 2.P.175.230; 2.P.175.231; 2.P.175.236;2.P.175.237; 2.P.175.238; 2.P.175.239; 2.P.175.154; 2.P.175.157;2.P.175.166; 2.P.175.169; 2.P.175.172; 2.P.175.175; 2.P.175.240;2.P.175.244; 2.P.240.228; 2.P.240.229; 2.P.240.230; 2.P.240.231;2.P.240.236; 2.P.240.237; 2.P.240.238; 2.P.240.239; 2.P.240.154;2.P.240.157; 2.P.240.166; 2.P.240.169; 2.P.240.172; 2.P.240.175;2.P.240.240; 2.P.240.244; 2.P.244.228; 2.P.244.229; 2.P.244.230;2.P.244.231; 2.P.244.236; 2.P.244.237; 2.P.244.238; 2.P.244.239;2.P.244.154; 2.P.244.157; 2.P.244.166; 2.P.244.169; 2.P.244.172;2.P.244.175; 2.P.244.240; 2.P.244.244; Prodrugs of 2.U 2.U.228.228;2.U.228.229; 2.U.228.230; 2.U.228.231; 2.U.228.236; 2.U.228.237;2.U.228.238; 2.U.228.239; 2.U.228.154; 2.U.228.157; 2.U.228.166;2.U.228.169; 2.U.228.172; 2.U.228.175; 2.U.228.240; 2.U.228.244;2.U.229.228; 2.U.229.229; 2.U.229.230; 2.U.229.231; 2.U.229.236;2.U.229.237; 2.U.229.238; 2.U.229.239; 2.U.229.154; 2.U.229.157;2.U.229.166; 2.U.229.169; 2.U.229.172; 2.U.229.175; 2.U.229.240;2.U.229.244; 2.U.230.228; 2.U.230.229; 2.U.230.230; 2.U.230.231;2.U.230.236; 2.U.230.237; 2.U.230.238; 2.U.230.239; 2.U.230.154;2.U.230.157; 2.U.230.166; 2.U.230.169; 2.U.230.172; 2.U.230.175;2.U.230.240; 2.U.230.244; 2.U.231.228; 2.U.231.229; 2.U.231.230;2.U.231.231; 2.U.231.236; 2.U.231.237; 2.U.231.238; 2.U.231.239;2.U.231.154; 2.U.231.157; 2.U.231.166; 2.U.231.169; 2.U.231.172;2.U.231.175; 2.U.231.240; 2.U.231.244; 2.U.236.228; 2.U.236.229;2.U.236.230; 2.U.236.231; 2.U.236.236; 2.U.236.237; 2.U.236.238;2.U.236.239; 2.U.236.154; 2.U.236.157; 2.U.236.166; 2.U.236.169;2.U.236.172; 2.U.236.175; 2.U.236.240; 2.U.236.244; 2.U.237.228;2.U.237.229; 2.U.237.230; 2.U.237.231; 2.U.237.236; 2.U.237.237;2.U.237.238; 2.U.237.239; 2.U.237.154; 2.U.237.157; 2.U.237.166;2.U.237.169; 2.U.237.172; 2.U.237.175; 2.U.237.240; 2.U.237.244;2.U.238.228; 2.U.238.229; 2.U.238.230; 2.U.238.231; 2.U.238.236;2.U.238.237; 2.U.238.238; 2.U.238.239; 2.U.238.154; 2.U.238.157;2.U.238.166; 2.U.238.169; 2.U.238.172; 2.U.238.175; 2.U.238.240;2.U.238.244; 2.U.239.228; 2.U.239.229; 2.U.239.230; 2.U.239.231;2.U.239.236; 2.U.239.237; 2.U.239.238; 2.U.239.239; 2.U.239.154;2.U.239.157; 2.U.239.166; 2.U.239.169; 2.U.239.172; 2.U.239.175;2.U.239.240; 2.U.239.244; 2.U.154.228; 2.U.154.229; 2.U.154.230;2.U.154.231; 2.U.154.236; 2.U.154.237; 2.U.154.238; 2.U.154.239;2.U.154.154; 2.U.154.157; 2.U.154.166; 2.U.154.169; 2.U.154.172;2.U.154.175; 2.U.154.240; 2.U.154.244; 2.U.157.228; 2.U.157.229;2.U.157.230; 2.U.157.231; 2.U.157.236; 2.U.157.237; 2.U.157.238;2.U.157.239; 2.U.157.154; 2.U.157.157; 2.U.157.166; 2.U.157.169;2.U.157.172; 2.U.157.175; 2.U.157.240; 2.U.157.244; 2.U.166.228;2.U.166.229; 2.U.166.230; 2.U.166.231; 2.U.166.236; 2.U.166.237;2.U.166.238; 2.U.166.239; 2.U.166.154; 2.U.166.157; 2.U.166.166;2.U.166.169; 2.U.166.172; 2.U.166.175; 2.U.166.240; 2.U.166.244;2.U.169.228; 2.U.169.229; 2.U.169.230; 2.U.169.231; 2.U.169.236;2.U.169.237; 2.U.169.238; 2.U.169.239; 2.U.169.154; 2.U.169.157;2.U.169.166; 2.U.169.169; 2.U.169.172; 2.U.169.175; 2.U.169.240;2.U.169.244; 2.U.172.228; 2.U.172.229; 2.U.172.230; 2.U.172.231;2.U.172.236; 2.U.172.237; 2.U.172.238; 2.U.172.239; 2.U.172.154;2.U.172.157; 2.U.172.166; 2.U.172.169; 2.U.172.172; 2.U.172.175;2.U.172.240; 2.U.172.244; 2.U.175.228; 2.U.175.229; 2.U.175.230;2.U.175.231; 2.U.175.236; 2.U.175.237; 2.U.175.238; 2.U.175.239;2.U.175.154; 2.U.175.157; 2.U.175.166; 2.U.175.169; 2.U.175.172;2.U.175.175; 2.U.175.240; 2.U.175.244; 2.U.240.228; 2.U.240.229;2.U.240.230; 2.U.240.231; 2.U.240.236; 2.U.240.237; 2.U.240.238;2.U.240.239; 2.U.240.154; 2.U.240.157; 2.U.240.166; 2.U.240.169;2.U.240.172; 2.U.240.175; 2.U.240.240; 2.U.240.244; 2.U.244.228;2.U.244.229; 2.U.244.230; 2.U.244.231; 2.U.244.236; 2.U.244.237;2.U.244.238; 2.U.244.239; 2.U.244.154; 2.U.244.157; 2.U.244.166;2.U.244.169; 2.U.244.172; 2.U.244.175; 2.U.244.240; 2.U.244.244;Prodrugs of 2.W 2.W.228.228; 2.W.228.229; 2.W.228.230; 2.W.228.231;2.W.228.236; 2.W.228.237; 2.W.228.238; 2.W.228.239; 2.W.228.154;2.W.228.157; 2.W.228.166; 2.W.228.169; 2.W.228.172; 2.W.228.175;2.W.228.240; 2.W.228.244; 2.W.229.228; 2.W.229.229; 2.W.229.230;2.W.229.231; 2.W.229.236; 2.W.229.237; 2.W.229.238; 2.W.229.239;2.W.229.154; 2.W.229.157; 2.W.229.166; 2.W.229.169; 2.W.229.172;2.W.229.175; 2.W.229.240; 2.W.229.244; 2.W.230.228; 2.W.230.229;2.W.230.230; 2.W.230.231; 2.W.230.236; 2.W.230.237; 2.W.230.238;2.W.230.239; 2.W.230.154; 2.W.230.157; 2.W.230.166; 2.W.230.169;2.W.230.172; 2.W.230.175; 2.W.230.240; 2.W.230.244; 2.W.231.228;2.W.231.229; 2.W.231.230; 2.W.231.231; 2.W.231.236; 2.W.231.237;2.W.231.238; 2.W.231.239; 2.W.231.154; 2.W.231.157; 2.W.231.166;2.W.231.169; 2.W.231.172; 2.W.231.175; 2.W.231.240; 2.W.231.244;2.W.236.228; 2.W.236.229; 2.W.236.230; 2.W.236.231; 2.W.236.236;2.W.236.237; 2.W.236.238; 2.W.236.239; 2.W.236.154; 2.W.236.157;2.W.236.166; 2.W.236.169; 2.W.236.172; 2.W.236.175; 2.W.236.240;2.W.236.244; 2.W.237.228; 2.W.237.229; 2.W.237.230; 2.W.237.231;2.W.237.236; 2.W.237.237; 2.W.237.238; 2.W.237.239; 2.W.237.154;2.W.237.157; 2.W.237.166; 2.W.237.169; 2.W.237.172; 2.W.237.175;2.W.237.240; 2.W.237.244; 2.W.238.228; 2.W.238.229; 2.W.238.230;2.W.238.231; 2.W.238.236; 2.W.238.237; 2.W.238.238; 2.W.238.239;2.W.238.154; 2.W.238.157; 2.W.238.166; 2.W.238.169; 2.W.238.172;2.W.238.175; 2.W.238.240; 2.W.238.244; 2.W.239.228; 2.W.239.229;2.W.239.230; 2.W.239.231; 2.W.239.236; 2.W.239.237; 2.W.239.238;2.W.239.239; 2.W.239.154; 2.W.239.157; 2.W.239.166; 2.W.239.169;2.W.239.172; 2.W.239.175; 2.W.239.240; 2.W.239.244; 2.W.154.228;2.W.154.229; 2.W.154.230; 2.W.154.231; 2.W.154.236; 2.W.154.237;2.W.154.238; 2.W.154.239; 2.W.154.154; 2.W.154.157; 2.W.154.166;2.W.154.169; 2.W.154.172; 2.W.154.175; 2.W.154.240; 2.W.154.244;2.W.157.228; 2.W.157.229; 2.W.157.230; 2.W.157.231; 2.W.157.236;2.W.157.237; 2.W.157.238; 2.W.157.239; 2.W.157.154; 2.W.157.157;2.W.157.166; 2.W.157.169; 2.W.157.172; 2.W.157.175; 2.W.157.240;2.W.157.244; 2.W.166.228; 2.W.166.229; 2.W.166.230; 2.W.166.231;2.W.166.236; 2.W.166.237; 2.W.166.238; 2.W.166.239; 2.W.166.154;2.W.166.157; 2.W.166.166; 2.W.166.169; 2.W.166.172; 2.W.166.175;2.W.166.240; 2.W.166.244; 2.W.169.228; 2.W.169.229; 2.W.169.230;2.W.169.231; 2.W.169.236; 2.W.169.237; 2.W.169.238; 2.W.169.239;2.W.169.154; 2.W.169.157; 2.W.169.166; 2.W.169.169; 2.W.169.172;2.W.169.175; 2.W.169.240; 2.W.169.244; 2.W.172.228; 2.W.172.229;2.W.172.230; 2.W.172.231; 2.W.172.236; 2.W.172.237; 2.W.172.238;2.W.172.239; 2.W.172.154; 2.W.172.157; 2.W.172.166; 2.W.172.169;2.W.172.172; 2.W.172.175; 2.W.172.240; 2.W.172.244; 2.W.175.228;2.W.175.229; 2.W.175.230; 2.W.175.231; 2.W.175.236; 2.W.175.237;2.W.175.238; 2.W.175.239; 2.W.175.154; 2.W.175.157; 2.W.175.166;2.W.175.169; 2.W.175.172; 2.W.175.175; 2.W.175.240; 2.W.175.244;2.W.240.228; 2.W.240.229; 2.W.240.230; 2.W.240.231; 2.W.240.236;2.W.240.237; 2.W.240.238; 2.W.240.239; 2.W.240.154; 2.W.240.157;2.W.240.166; 2.W.240.169; 2.W.240.172; 2.W.240.175; 2.W.240.240;2.W.240.244; 2.W.244.228; 2.W.244.229; 2.W.244.230; 2.W.244.231;2.W.244.236; 2.W.244.237; 2.W.244.238; 2.W.244.239; 2.W.244.154;2.W.244.157; 2.W.244.166; 2.W.244.169; 2.W.244.172; 2.W.244.175;2.W.244.240; 2.W.244.244; Prodrugs of 2.Y 2.Y.228.228; 2.Y.228.229;2.Y.228.230; 2.Y.228.231; 2.Y.228.236; 2.Y.228.237; 2.Y.228.238;2.Y.228.239; 2.Y.228.154; 2.Y.228.157; 2.Y.228.166; 2.Y.228.169;2.Y.228.172; 2.Y.228.175; 2.Y.228.240; 2.Y.228.244; 2.Y.229.228;2.Y.229.229; 2.Y.229.230; 2.Y.229.231; 2.Y.229.236; 2.Y.229.237;2.Y.229.238; 2.Y.229.239; 2.Y.229.154; 2.Y.229.157; 2.Y.229.166;2.Y.229.169; 2.Y.229.172; 2.Y.229.175; 2.Y.229.240; 2.Y.229.244;2.Y.230.228; 2.Y.230.229; 2.Y.230.230; 2.Y.230.231; 2.Y.230.236;2.Y.230.237; 2.Y.230.238; 2.Y.230.239; 2.Y.230.154; 2.Y.230.157;2.Y.230.166; 2.Y.230.169; 2.Y.230.172; 2.Y.230.175; 2.Y.230.240;2.Y.230.244; 2.Y.231.228; 2.Y.231.229; 2.Y.231.230; 2.Y.231.231;2.Y.231.236; 2.Y.231.237; 2.Y.231.238; 2.Y.231.239; 2.Y.231.154;2.Y.231.157; 2.Y.231.166; 2.Y.231.169; 2.Y.231.172; 2.Y.231.175;2.Y.231.240; 2.Y.231.244; 2.Y.236.228; 2.Y.236.229; 2.Y.236.230;2.Y.236.231; 2.Y.236.236; 2.Y.236.237; 2.Y.236.238; 2.Y.236.239;2.Y.236.154; 2.Y.236.157; 2.Y.236.166; 2.Y.236.169; 2.Y.236.172;2.Y.236.175; 2.Y.236.240; 2.Y.236.244; 2.Y.237.228; 2.Y.237.229;2.Y.237.230; 2.Y.237.231; 2.Y.237.236; 2.Y.237.237; 2.Y.237.238;2.Y.237.239; 2.Y.237.154; 2.Y.237.157; 2.Y.237.166; 2.Y.237.169;2.Y.237.172; 2.Y.237.175; 2.Y.237.240; 2.Y.237.244; 2.Y.238.228;2.Y.238.229; 2.Y.238.230; 2.Y.238.231; 2.Y.238.236; 2.Y.238.237;2.Y.238.238; 2.Y.238.239; 2.Y.238.154; 2.Y.238.157; 2.Y.238.166;2.Y.238.169; 2.Y.238.172; 2.Y.238.175; 2.Y.238.240; 2.Y.238.244;2.Y.239.228; 2.Y.239.229; 2.Y.239.230; 2.Y.239.231; 2.Y.239.236;2.Y.239.237; 2.Y.239.238; 2.Y.239.239; 2.Y.239.154; 2.Y.239.157;2.Y.239.166; 2.Y.239.169; 2.Y.239.172; 2.Y.239.175; 2.Y.239.240;2.Y.239.244; 2.Y.154.228; 2.Y.154.229; 2.Y.154.230; 2.Y.154.231;2.Y.154.236; 2.Y.154.237; 2.Y.154.238; 2.Y.154.239; 2.Y.154.154;2.Y.154.157; 2.Y.154.166; 2.Y.154.169; 2.Y.154.172; 2.Y.154.175;2.Y.154.240; 2.Y.154.244; 2.Y.157.228; 2.Y.157.229; 2.Y.157.230;2.Y.157.231; 2.Y.157.236; 2.Y.157.237; 2.Y.157.238; 2.Y.157.239;2.Y.157.154; 2.Y.157.157; 2.Y.157.166; 2.Y.157.169; 2.Y.157.172;2.Y.157.175; 2.Y.157.240; 2.Y.157.244; 2.Y.166.228; 2.Y.166.229;2.Y.166.230; 2.Y.166.231; 2.Y.166.236; 2.Y.166.237; 2.Y.166.238;2.Y.166.239; 2.Y.166.154; 2.Y.166.157; 2.Y.166.166; 2.Y.166.169;2.Y.166.172; 2.Y.166.175; 2.Y.166.240; 2.Y.166.244; 2.Y.169.228;2.Y.169.229; 2.Y.169.230; 2.Y.169.231; 2.Y.169.236; 2.Y.169.237;2.Y.169.238; 2.Y.169.239; 2.Y.169.154; 2.Y.169.157; 2.Y.169.166;2.Y.169.169; 2.Y.169.172; 2.Y.169.175; 2.Y.169.240; 2.Y.169.244;2.Y.172.228; 2.Y.172.229; 2.Y.172.230; 2.Y.172.231; 2.Y.172.236;2.Y.172.237; 2.Y.172.238; 2.Y.172.239; 2.Y.172.154; 2.Y.172.157;2.Y.172.166; 2.Y.172.169; 2.Y.172.172; 2.Y.172.175; 2.Y.172.240;2.Y.172.244; 2.Y.175.228; 2.Y.175.229; 2.Y.175.230; 2.Y.175.231;2.Y.175.236; 2.Y.175.237; 2.Y.175.238; 2.Y.175.239; 2.Y.175.154;2.Y.175.157; 2.Y.175.166; 2.Y.175.169; 2.Y.175.172; 2.Y.175.175;2.Y.175.240; 2.Y.175.244; 2.Y.240.228; 2.Y.240.229; 2.Y.240.230;2.Y.240.231; 2.Y.240.236; 2.Y.240.237; 2.Y.240.238; 2.Y.240.239;2.Y.240.154; 2.Y.240.157; 2.Y.240.166; 2.Y.240.169; 2.Y.240.172;2.Y.240.175; 2.Y.240.240; 2.Y.240.244; 2.Y.244.228; 2.Y.244.229;2.Y.244.230; 2.Y.244.231; 2.Y.244.236; 2.Y.244.237; 2.Y.244.238;2.Y.244.239; 2.Y.244.154; 2.Y.244.157; 2.Y.244.166; 2.Y.244.169;2.Y.244.172; 2.Y.244.175; 2.Y.244.240; 2.Y.244.244; Prodrugs of 3.B3.B.228.228; 3.B.228.229; 3.B.228.230; 3.B.228.231; 3.B.228.236;3.B.228.237; 3.B.228.238; 3.B.228.239; 3.B.228.154; 3.B.228.157;3.B.228.166; 3.B.228.169; 3.B.228.172; 3.B.228.175; 3.B.228.240;3.B.228.244; 3.B.229.228; 3.B.229.229; 3.B.229.230; 3.B.229.231;3.B.229.236; 3.B.229.237; 3.B.229.238; 3.B.229.239; 3.B.229.154;3.B.229.157; 3.B.229.166; 3.B.229.169; 3.B.229.172; 3.B.229.175;3.B.229.240; 3.B.229.244; 3.B.230.228; 3.B.230.229; 3.B.230.230;3.B.230.231; 3.B.230.236; 3.B.230.237; 3.B.230.238; 3.B.230.239;3.B.230.154; 3.B.230.157; 3.B.230.166; 3.B.230.169; 3.B.230.172;3.B.230.175; 3.B.230.240; 3.B.230.244; 3.B.231.228; 3.B.231.229;3.B.231.230; 3.B.231.231; 3.B.231.236; 3.B.231.237; 3.B.231.238;3.B.231.239; 3.B.231.154; 3.B.231.157; 3.B.231.166; 3.B.231.169;3.B.231.172; 3.B.231.175; 3.B.231.240; 3.B.231.244; 3.B.236.228;3.B.236.229; 3.B.236.230; 3.B.236.231; 3.B.236.236; 3.B.236.237;3.B.236.238; 3.B.236.239; 3.B.236.154; 3.B.236.157; 3.B.236.166;3.B.236.169; 3.B.236.172; 3.B.236.175; 3.B.236.240; 3.B.236.244;3.B.237.228; 3.B.237.229; 3.B.237.230; 3.B.237.231; 3.B.237.236;3.B.237.237; 3.B.237.238; 3.B.237.239; 3.B.237.154; 3.B.237.157;3.B.237.166; 3.B.237.169; 3.B.237.172; 3.B.237.175; 3.B.237.240;3.B.237.244; 3.B.238.228; 3.B.238.229; 3.B.238.230; 3.B.238.231;3.B.238.236; 3.B.238.237; 3.B.238.238; 3.B.238.239; 3.B.238.154;3.B.238.157; 3.B.238.166; 3.B.238.169; 3.B.238.172; 3.B.238.175;3.B.238.240; 3.B.238.244; 3.B.239.228; 3.B.239.229; 3.B.239.230;3.B.239.231; 3.B.239.236; 3.B.239.237; 3.B.239.238; 3.B.239.239;3.B.239.154; 3.B.239.157; 3.B.239.166; 3.B.239.169; 3.B.239.172;3.B.239.175; 3.B.239.240; 3.B.239.244; 3.B.154.228; 3.B.154.229;3.B.154.230; 3.B.154.231; 3.B.154.236; 3.B.154.237; 3.B.154.238;3.B.154.239; 3.B.154.154; 3.B.154.157; 3.B.154.166; 3.B.154.169;3.B.154.172; 3.B.154.175; 3.B.154.240; 3.B.154.244; 3.B.157.228;3.B.157.229; 3.B.157.230; 3.B.157.231; 3.B.157.236; 3.B.157.237;3.B.157.238; 3.B.157.239; 3.B.157.154; 3.B.157.157; 3.B.157.166;3.B.157.169; 3.B.157.172; 3.B.157.175; 3.B.157.240; 3.B.157.244;3.B.166.228; 3.B.166.229; 3.B.166.230; 3.B.166.231; 3.B.166.236;3.B.166.237; 3.B.166.238; 3.B.166.239; 3.B.166.154; 3.B.166.157;3.B.166.166; 3.B.166.169; 3.B.166.172; 3.B.166.175; 3.B.166.240;3.B.166.244; 3.B.169.228; 3.B.169.229; 3.B.169.230; 3.B.169.231;3.B.169.236; 3.B.169.237; 3.B.169.238; 3.B.169.239; 3.B.169.154;3.B.169.157; 3.B.169.166; 3.B.169.169; 3.B.169.172; 3.B.169.175;3.B.169.240; 3.B.169.244; 3.B.172.228; 3.B.172.229; 3.B.172.230;3.B.172.231; 3.B.172.236; 3.B.172.237; 3.B.172.238; 3.B.172.239;3.B.172.154; 3.B.172.157; 3.B.172.166; 3.B.172.169; 3.B.172.172;3.B.172.175; 3.B.172.240; 3.B.172.244; 3.B.175.228; 3.B.175.229;3.B.175.230; 3.B.175.231; 3.B.175.236; 3.B.175.237; 3.B.175.238;3.B.175.239; 3.B.175.154; 3.B.175.157; 3.B.175.166; 3.B.175.169;3.B.175.172; 3.B.175.175; 3.B.175.240; 3.B.175.244; 3.B.240.228;3.B.240.229; 3.B.240.230; 3.B.240.231; 3.B.240.236; 3.B.240.237;3.B.240.238; 3.B.240.239; 3.B.240.154; 3.B.240.157; 3.B.240.166;3.B.240.169; 3.B.240.172; 3.B.240.175; 3.B.240.240; 3.B.240.244;3.B.244.228; 3.B.244.229; 3.B.244.230; 3.B.244.231; 3.B.244.236;3.B.244.237; 3.B.244.238; 3.B.244.239; 3.B.244.154; 3.B.244.157;3.B.244.166; 3.B.244.169; 3.B.244.172; 3.B.244.175; 3.B.244.240;3.B.244.244; Prodrugs of 3.D 3.D.228.228; 3.D.228.229; 3.D.228.230;3.D.228.231; 3.D.228.236; 3.D.228.237; 3.D.228.238; 3.D.228.239;3.D.228.154; 3.D.228.157; 3.D.228.166; 3.D.228.169; 3.D.228.172;3.D.228.175; 3.D.228.240; 3.D.228.244; 3.D.229.228; 3.D.229.229;3.D.229.230; 3.D.229.231; 3.D.229.236; 3.D.229.237; 3.D.229.238;3.D.229.239; 3.D.229.154; 3.D.229.157; 3.D.229.166; 3.D.229.169;3.D.229.172; 3.D.229.175; 3.D.229.240; 3.D.229.244; 3.D.230.228;3.D.230.229; 3.D.230.230; 3.D.230.231; 3.D.230.236; 3.D.230.237;3.D.230.238; 3.D.230.239; 3.D.230.154; 3.D.230.157; 3.D.230.166;3.D.230.169; 3.D.230.172; 3.D.230.175; 3.D.230.240; 3.D.230.244;3.D.231.228; 3.D.231.229; 3.D.231.230; 3.D.231.231; 3.D.231.236;3.D.231.237; 3.D.231.238; 3.D.231.239; 3.D.231.154; 3.D.231.157;3.D.231.166; 3.D.231.169; 3.D.231.172; 3.D.231.175; 3.D.231.240;3.D.231.244; 3.D.236.228; 3.D.236.229; 3.D.236.230; 3.D.236.231;3.D.236.236; 3.D.236.237; 3.D.236.238; 3.D.236.239; 3.D.236.154;3.D.236.157; 3.D.236.166; 3.D.236.169; 3.D.236.172; 3.D.236.175;3.D.236.240; 3.D.236.244; 3.D.237.228; 3.D.237.229; 3.D.237.230;3.D.237.231; 3.D.237.236; 3.D.237.237; 3.D.237.238; 3.D.237.239;3.D.237.154; 3.D.237.157; 3.D.237.166; 3.D.237.169; 3.D.237.172;3.D.237.175; 3.D.237.240; 3.D.237.244; 3.D.238.228; 3.D.238.229;3.D.238.230; 3.D.238.231; 3.D.238.236; 3.D.238.237; 3.D.238.238;3.D.238.239; 3.D.238.154; 3.D.238.157; 3.D.238.166; 3.D.238.169;3.D.238.172; 3.D.238.175; 3.D.238.240; 3.D.238.244; 3.D.239.228;3.D.239.229; 3.D.239.230; 3.D.239.231; 3.D.239.236; 3.D.239.237;3.D.239.238; 3.D.239.239; 3.D.239.154; 3.D.239.157; 3.D.239.166;3.D.239.169; 3.D.239.172; 3.D.239.175; 3.D.239.240; 3.D.239.244;3.D.154.228; 3.D.154.229; 3.D.154.230; 3.D.154.231; 3.D.154.236;3.D.154.237; 3.D.154.238; 3.D.154.239; 3.D.154.154; 3.D.154.157;3.D.154.166; 3.D.154.169; 3.D.154.172; 3.D.154.175; 3.D.154.240;3.D.154.244; 3.D.157.228; 3.D.157.229; 3.D.157.230; 3.D.157.231;3.D.157.236; 3.D.157.237; 3.D.157.238; 3.D.157.239; 3.D.157.154;3.D.157.157; 3.D.157.166; 3.D.157.169; 3.D.157.172; 3.D.157.175;3.D.157.240; 3.D.157.244; 3.D.166.228; 3.D.166.229; 3.D.166.230;3.D.166.231; 3.D.166.236; 3.D.166.237; 3.D.166.238; 3.D.166.239;3.D.166.154; 3.D.166.157; 3.D.166.166; 3.D.166.169; 3.D.166.172;3.D.166.175; 3.D.166.240; 3.D.166.244; 3.D.169.228; 3.D.169.229;3.D.169.230; 3.D.169.231; 3.D.169.236; 3.D.169.237; 3.D.169.238;3.D.169.239; 3.D.169.154; 3.D.169.157; 3.D.169.166; 3.D.169.169;3.D.169.172; 3.D.169.175; 3.D.169.240; 3.D.169.244; 3.D.172.228;3.D.172.229; 3.D.172.230; 3.D.172.231; 3.D.172.236; 3.D.172.237;3.D.172.238; 3.D.172.239; 3.D.172.154; 3.D.172.157; 3.D.172.166;3.D.172.169; 3.D.172.172; 3.D.172.175; 3.D.172.240; 3.D.172.244;3.D.175.228; 3.D.175.229; 3.D.175.230; 3.D.175.231; 3.D.175.236;3.D.175.237; 3.D.175.238; 3.D.175.239; 3.D.175.154; 3.D.175.157;3.D.175.166; 3.D.175.169; 3.D.175.172; 3.D.175.175; 3.D.175.240;3.D.175.244; 3.D.240.228; 3.D.240.229; 3.D.240.230; 3.D.240.231;3.D.240.236; 3.D.240.237; 3.D.240.238; 3.D.240.239; 3.D.240.154;3.D.240.157; 3.D.240.166; 3.D.240.169; 3.D.240.172; 3.D.240.175;3.D.240.240; 3.D.240.244; 3.D.244.228; 3.D.244.229; 3.D.244.230;3.D.244.231; 3.D.244.236; 3.D.244.237; 3.D.244.238; 3.D.244.239;3.D.244.154; 3.D.244.157; 3.D.244.166; 3.D.244.169; 3.D.244.172;3.D.244.175; 3.D.244.240; 3.D.244.244; Prodrugs of 3.E 3.E.228.228;3.E.228.229; 3.E.228.230; 3.E.228.231; 3.E.228.236; 3.E.228.237;3.E.228.238; 3.E.228.239; 3.E.228.154; 3.E.228.157; 3.E.228.166;3.E.228.169; 3.E.228.172; 3.E.228.175; 3.E.228.240; 3.E.228.244;3.E.229.228; 3.E.229.229; 3.E.229.230; 3.E.229.231; 3.E.229.236;3.E.229.237; 3.E.229.238; 3.E.229.239; 3.E.229.154; 3.E.229.157;3.E.229.166; 3.E.229.169; 3.E.229.172; 3.E.229.175; 3.E.229.240;3.E.229.244; 3.E.230.228; 3.E.230.229; 3.E.230.230; 3.E.230.231;3.E.230.236; 3.E.230.237; 3.E.230.238; 3.E.230.239; 3.E.230.154;3.E.230.157; 3.E.230.166; 3.E.230.169; 3.E.230.172; 3.E.230.175;3.E.230.240; 3.E.230.244; 3.E.231.228; 3.E.231.229; 3.E.231.230;3.E.231.231; 3.E.231.236; 3.E.231.237; 3.E.231.238; 3.E.231.239;3.E.231.154; 3.E.231.157; 3.E.231.166; 3.E.231.169; 3.E.231.172;3.E.231.175; 3.E.231.240; 3.E.231.244; 3.E.236.228; 3.E.236.229;3.E.236.230; 3.E.236.231; 3.E.236.236; 3.E.236.237; 3.E.236.238;3.E.236.239; 3.E.236.154; 3.E.236.157; 3.E.236.166; 3.E.236.169;3.E.236.172; 3.E.236.175; 3.E.236.240; 3.E.236.244; 3.E.237.228;3.E.237.229; 3.E.237.230; 3.E.237.231; 3.E.237.236; 3.E.237.237;3.E.237.238; 3.E.237.239; 3.E.237.154; 3.E.237.157; 3.E.237.166;3.E.237.169; 3.E.237.172; 3.E.237.175; 3.E.237.240; 3.E.237.244;3.E.238.228; 3.E.238.229; 3.E.238.230; 3.E.238.231; 3.E.238.236;3.E.238.237; 3.E.238.238; 3.E.238.239; 3.E.238.154; 3.E.238.157;3.E.238.166; 3.E.238.169; 3.E.238.172; 3.E.238.175; 3.E.238.240;3.E.238.244; 3.E.239.228; 3.E.239.229; 3.E.239.230; 3.E.239.231;3.E.239.236; 3.E.239.237; 3.E.239.238; 3.E.239.239; 3.E.239.154;3.E.239.157; 3.E.239.166; 3.E.239.169; 3.E.239.172; 3.E.239.175;3.E.239.240; 3.E.239.244; 3.E.154.228; 3.E.154.229; 3.E.154.230;3.E.154.231; 3.E.154.236; 3.E.154.237; 3.E.154.238; 3.E.154.239;3.E.154.154; 3.E.154.157; 3.E.154.166; 3.E.154.169; 3.E.154.172;3.E.154.175; 3.E.154.240; 3.E.154.244; 3.E.157.228; 3.E.157.229;3.E.157.230; 3.E.157.231; 3.E.157.236; 3.E.157.237; 3.E.157.238;3.E.157.239; 3.E.157.154; 3.E.157.157; 3.E.157.166; 3.E.157.169;3.E.157.172; 3.E.157.175; 3.E.157.240; 3.E.157.244; 3.E.166.228;3.E.166.229; 3.E.166.230; 3.E.166.231; 3.E.166.236; 3.E.166.237;3.E.166.238; 3.E.166.239; 3.E.166.154; 3.E.166.157; 3.E.166.166;3.E.166.169; 3.E.166.172; 3.E.166.175; 3.E.166.240; 3.E.166.244;3.E.169.228; 3.E.169.229; 3.E.169.230; 3.E.169.231; 3.E.169.236;3.E.169.237; 3.E.169.238; 3.E.169.239; 3.E.169.154; 3.E.169.157;3.E.169.166; 3.E.169.169; 3.E.169.172; 3.E.169.175; 3.E.169.240;3.E.169.244; 3.E.172.228; 3.E.172.229; 3.E.172.230; 3.E.172.231;3.E.172.236; 3.E.172.237; 3.E.172.238; 3.E.172.239; 3.E.172.154;3.E.172.157; 3.E.172.166; 3.E.172.169; 3.E.172.172; 3.E.172.175;3.E.172.240; 3.E.172.244; 3.E.175.228; 3.E.175.229; 3.E.175.230;3.E.175.231; 3.E.175.236; 3.E.175.237; 3.E.175.238; 3.E.175.239;3.E.175.154; 3.E.175.157; 3.E.175.166; 3.E.175.169; 3.E.175.172;3.E.175.175; 3.E.175.240; 3.E.175.244; 3.E.240.228; 3.E.240.229;3.E.240.230; 3.E.240.231; 3.E.240.236; 3.E.240.237; 3.E.240.238;3.E.240.239; 3.E.240.154; 3.E.240.157; 3.E.240.166; 3.E.240.169;3.E.240.172; 3.E.240.175; 3.E.240.240; 3.E.240.244; 3.E.244.228;3.E.244.229; 3.E.244.230; 3.E.244.231; 3.E.244.236; 3.E.244.237;3.E.244.238; 3.E.244.239; 3.E.244.154; 3.E.244.157; 3.E.244.166;3.E.244.169; 3.E.244.172; 3.E.244.175; 3.E.244.240; 3.E.244.244;Prodrugs of 3.G 3.G.228.228; 3.G.228.229; 3.G.228.230; 3.G.228.231;3.G.228.236; 3.G.228.237; 3.G.228.238; 3.G.228.239; 3.G.228.154;3.G.228.157; 3.G.228.166; 3.G.228.169; 3.G.228.172; 3.G.228.175;3.G.228.240; 3.G.228.244; 3.G.229.228; 3.G.229.229; 3.G.229.230;3.G.229.231; 3.G.229.236; 3.G.229.237; 3.G.229.238; 3.G.229.239;3.G.229.154; 3.G.229.157; 3.G.229.166; 3.G.229.169; 3.G.229.172;3.G.229.175; 3.G.229.240; 3.G.229.244; 3.G.230.228; 3.G.230.229;3.G.230.230; 3.G.230.231; 3.G.230.236; 3.G.230.237; 3.G.230.238;3.G.230.239; 3.G.230.154; 3.G.230.157; 3.G.230.166; 3.G.230.169;3.G.230.172; 3.G.230.175; 3.G.230.240; 3.G.230.244; 3.G.231.228;3.G.231.229; 3.G.231.230; 3.G.231.231; 3.G.231.236; 3.G.231.237;3.G.231.238; 3.G.231.239; 3.G.231.154; 3.G.231.157; 3.G.231.166;3.G.231.169; 3.G.231.172; 3.G.231.175; 3.G.231.240; 3.G.231.244;3.G.236.228; 3.G.236.229; 3.G.236.230; 3.G.236.231; 3.G.236.236;3.G.236.237; 3.G.236.238; 3.G.236.239; 3.G.236.154; 3.G.236.157;3.G.236.166; 3.G.236.169; 3.G.236.172; 3.G.236.175; 3.G.236.240;3.G.236.244; 3.G.237.228; 3.G.237.229; 3.G.237.230; 3.G.237.231;3.G.237.236; 3.G.237.237; 3.G.237.238; 3.G.237.239; 3.G.237.154;3.G.237.157; 3.G.237.166; 3.G.237.169; 3.G.237.172; 3.G.237.175;3.G.237.240; 3.G.237.244; 3.G.238.228; 3.G.238.229; 3.G.238.230;3.G.238.231; 3.G.238.236; 3.G.238.237; 3.G.238.238; 3.G.238.239;3.G.238.154; 3.G.238.157; 3.G.238.166; 3.G.238.169; 3.G.238.172;3.G.238.175; 3.G.238.240; 3.G.238.244; 3.G.239.228; 3.G.239.229;3.G.239.230; 3.G.239.231; 3.G.239.236; 3.G.239.237; 3.G.239.238;3.G.239.239; 3.G.239.154; 3.G.239.157; 3.G.239.166; 3.G.239.169;3.G.239.172; 3.G.239.175; 3.G.239.240; 3.G.239.244; 3.G.154.228;3.G.154.229; 3.G.154.230; 3.G.154.231; 3.G.154.236; 3.G.154.237;3.G.154.238; 3.G.154.239; 3.G.154.154; 3.G.154.157; 3.G.154.166;3.G.154.169; 3.G.154.172; 3.G.154.175; 3.G.154.240; 3.G.154.244;3.G.157.228; 3.G.157.229; 3.G.157.230; 3.G.157.231; 3.G.157.236;3.G.157.237; 3.G.157.238; 3.G.157.239; 3.G.157.154; 3.G.157.157;3.G.157.166; 3.G.157.169; 3.G.157.172; 3.G.157.175; 3.G.157.240;3.G.157.244; 3.G.166.228; 3.G.166.229; 3.G.166.230; 3.G.166.231;3.G.166.236; 3.G.166.237; 3.G.166.238; 3.G.166.239; 3.G.166.154;3.G.166.157; 3.G.166.166; 3.G.166.169; 3.G.166.172; 3.G.166.175;3.G.166.240; 3.G.166.244; 3.G.169.228; 3.G.169.229; 3.G.169.230;3.G.169.231; 3.G.169.236; 3.G.169.237; 3.G.169.238; 3.G.169.239;3.G.169.154; 3.G.169.157; 3.G.169.166; 3.G.169.169; 3.G.169.172;3.G.169.175; 3.G.169.240; 3.G.169.244; 3.G.172.228; 3.G.172.229;3.G.172.230; 3.G.172.231; 3.G.172.236; 3.G.172.237; 3.G.172.238;3.G.172.239; 3.G.172.154; 3.G.172.157; 3.G.172.166; 3.G.172.169;3.G.172.172; 3.G.172.175; 3.G.172.240; 3.G.172.244; 3.G.175.228;3.G.175.229; 3.G.175.230; 3.G.175.231; 3.G.175.236; 3.G.175.237;3.G.175.238; 3.G.175.239; 3.G.175.154; 3.G.175.157; 3.G.175.166;3.G.175.169; 3.G.175.172; 3.G.175.175; 3.G.175.240; 3.G.175.244;3.G.240.228; 3.G.240.229; 3.G.240.230; 3.G.240.231; 3.G.240.236;3.G.240.237; 3.G.240.238; 3.G.240.239; 3.G.240.154; 3.G.240.157;3.G.240.166; 3.G.240.169; 3.G.240.172; 3.G.240.175; 3.G.240.240;3.G.240.244; 3.G.244.228; 3.G.244.229; 3.G.244.230; 3.G.244.231;3.G.244.236; 3.G.244.237; 3.G.244.238; 3.G.244.239; 3.G.244.154;3.G.244.157; 3.G.244.166; 3.G.244.169; 3.G.244.172; 3.G.244.175;3.G.244.240; 3.G.244.244; Prodrugs of 3.I 3.I.228.228; 3.I.228.229;3.I.228.230; 3.I.228.231; 3.I.228.236; 3.I.228.237; 3.I.228.238;3.I.228.239; 3.I.228.154; 3.I.228.157; 3.I.228.166; 3.I.228.169;3.I.228.172; 3.I.228.175; 3.I.228.240; 3.I.228.244; 3.I.229.228;3.I.229.229; 3.I.229.230; 3.I.229.231; 3.I.229.236; 3.I.229.237;3.I.229.238; 3.I.229.239; 3.I.229.154; 3.I.229.157; 3.I.229.166;3.I.229.169; 3.I.229.172; 3.I.229.175; 3.I.229.240; 3.I.229.244;3.I.230.228; 3.I.230.229; 3.I.230.230; 3.I.230.231; 3.I.230.236;3.I.230.237; 3.I.230.238; 3.I.230.239; 3.I.230.154; 3.I.230.157;3.I.230.166; 3.I.230.169; 3.I.230.172; 3.I.230.175; 3.I.230.240;3.I.230.244; 3.I.231.228; 3.I.231.229; 3.I.231.230; 3.I.231.231;3.I.231.236; 3.I.231.237; 3.I.231.238; 3.I.231.239; 3.I.231.154;3.I.231.157; 3.I.231.166; 3.I.231.169; 3.I.231.172; 3.I.231.175;3.I.231.240; 3.I.231.244; 3.I.236.228; 3.I.236.229; 3.I.236.230;3.I.236.231; 3.I.236.236; 3.I.236.237; 3.I.236.238; 3.I.236.239;3.I.236.154; 3.I.236.157; 3.I.236.166; 3.I.236.169; 3.I.236.172;3.I.236.175; 3.I.236.240; 3.I.236.244; 3.I.237.228; 3.I.237.229;3.I.237.230; 3.I.237.231; 3.I.237.236; 3.I.237.237; 3.I.237.238;3.I.237.239; 3.I.237.154; 3.I.237.157; 3.I.237.166; 3.I.237.169;3.I.237.172; 3.I.237.175; 3.I.237.240; 3.I.237.244; 3.I.238.228;3.I.238.229; 3.I.238.230; 3.I.238.231; 3.I.238.236; 3.I.238.237;3.I.238.238; 3.I.238.239; 3.I.238.154; 3.I.238.157; 3.I.238.166;3.I.238.169; 3.I.238.172; 3.I.238.175; 3.I.238.240; 3.I.238.244;3.I.239.228; 3.I.239.229; 3.I.239.230; 3.I.239.231; 3.I.239.236;3.I.239.237; 3.I.239.238; 3.I.239.239; 3.I.239.154; 3.I.239.157;3.I.239.166; 3.I.239.169; 3.I.239.172; 3.I.239.175; 3.I.239.240;3.I.239.244; 3.I.154.228; 3.I.154.229; 3.I.154.230; 3.I.154.231;3.I.154.236; 3.I.154.237; 3.I.154.238; 3.I.154.239; 3.I.154.154;3.I.154.157; 3.I.154.166; 3.I.154.169; 3.I.154.172; 3.I.154.175;3.I.154.240; 3.I.154.244; 3.I.157.228; 3.I.157.229; 3.I.157.230;3.I.157.231; 3.I.157.236; 3.I.157.237; 3.I.157.238; 3.I.157.239;3.I.157.154; 3.I.157.157; 3.I.157.166; 3.I.157.169; 3.I.157.172;3.I.157.175; 3.I.157.240; 3.I.157.244; 3.I.166.228; 3.I.166.229;3.I.166.230; 3.I.166.231; 3.I.166.236; 3.I.166.237; 3.I.166.238;3.I.166.239; 3.I.166.154; 3.I.166.157; 3.I.166.166; 3.I.166.169;3.I.166.172; 3.I.166.175; 3.I.166.240; 3.I.166.244; 3.I.169.228;3.I.169.229; 3.I.169.230; 3.I.169.231; 3.I.169.236; 3.I.169.237;3.I.169.238; 3.I.169.239; 3.I.169.154; 3.I.169.157; 3.I.169.166;3.I.169.169; 3.I.169.172; 3.I.169.175; 3.I.169.240; 3.I.169.244;3.I.172.228; 3.I.172.229; 3.I.172.230; 3.I.172.231; 3.I.172.236;3.I.172.237; 3.I.172.238; 3.I.172.239; 3.I.172.154; 3.I.172.157;3.I.172.166; 3.I.172.169; 3.I.172.172; 3.I.172.175; 3.I.172.240;3.I.172.244; 3.I.175.228; 3.I.175.229; 3.I.175.230; 3.I.175.231;3.I.175.236; 3.I.175.237; 3.I.175.238; 3.I.175.239; 3.I.175.154;3.I.175.157; 3.I.175.166; 3.I.175.169; 3.I.175.172; 3.I.175.175;3.I.175.240; 3.I.175.244; 3.I.240.228; 3.I.240.229; 3.I.240.230;3.I.240.231; 3.I.240.236; 3.I.240.237; 3.I.240.238; 3.I.240.239;3.I.240.154; 3.I.240.157; 3.I.240.166; 3.I.240.169; 3.I.240.172;3.I.240.175; 3.I.240.240; 3.I.240.244; 3.I.244.228; 3.I.244.229;3.I.244.230; 3.I.244.231; 3.I.244.236; 3.I.244.237; 3.I.244.238;3.I.244.239; 3.I.244.154; 3.I.244.157; 3.I.244.166; 3.I.244.169;3.I.244.172; 3.I.244.175; 3.I.244.240; 3.I.244.244; Prodrugs of 3.J3.J.228.228; 3.J.228.229; 3.J.228.230; 3.J.228.231; 3.J.228.236;3.J.228.237; 3.J.228.238; 3.J.228.239; 3.J.228.154; 3.J.228.157;3.J.228.166; 3.J.228.169; 3.J.228.172; 3.J.228.175; 3.J.228.240;3.J.228.244; 3.J.229.228; 3.J.229.229; 3.J.229.230; 3.J.229.231;3.J.229.236; 3.J.229.237; 3.J.229.238; 3.J.229.239; 3.J.229.154;3.J.229.157; 3.J.229.166; 3.J.229.169; 3.J.229.172; 3.J.229.175;3.J.229.240; 3.J.229.244; 3.J.230.228; 3.J.230.229; 3.J.230.230;3.J.230.231; 3.J.230.236; 3.J.230.237; 3.J.230.238; 3.J.230.239;3.J.230.154; 3.J.230.157; 3.J.230.166; 3.J.230.169; 3.J.230.172;3.J.230.175; 3.J.230.240; 3.J.230.244; 3.J.231.228; 3.J.231.229;3.J.231.230; 3.J.231.231; 3.J.231.236; 3.J.231.237; 3.J.231.238;3.J.231.239; 3.J.231.154; 3.J.231.157; 3.J.231.166; 3.J.231.169;3.J.231.172; 3.J.231.175; 3.J.231.240; 3.J.231.244; 3.J.236.228;3.J.236.229; 3.J.236.230; 3.J.236.231; 3.J.236.236; 3.J.236.237;3.J.236.238; 3.J.236.239; 3.J.236.154; 3.J.236.157; 3.J.236.166;3.J.236.169; 3.J.236.172; 3.J.236.175; 3.J.236.240; 3.J.236.244;3.J.237.228; 3.J.237.229; 3.J.237.230; 3.J.237.231; 3.J.237.236;3.J.237.237; 3.J.237.238; 3.J.237.239; 3.J.237.154; 3.J.237.157;3.J.237.166; 3.J.237.169; 3.J.237.172; 3.J.237.175; 3.J.237.240;3.J.237.244; 3.J.238.228; 3.J.238.229; 3.J.238.230; 3.J.238.231;3.J.238.236; 3.J.238.237; 3.J.238.238; 3.J.238.239; 3.J.238.154;3.J.238.157; 3.J.238.166; 3.J.238.169; 3.J.238.172; 3.J.238.175;3.J.238.240; 3.J.238.244; 3.J.239.228; 3.J.239.229; 3.J.239.230;3.J.239.231; 3.J.239.236; 3.J.239.237; 3.J.239.238; 3.J.239.239;3.J.239.154; 3.J.239.157; 3.J.239.166; 3.J.239.169; 3.J.239.172;3.J.239.175; 3.J.239.240; 3.J.239.244; 3.J.154.228; 3.J.154.229;3.J.154.230; 3.J.154.231; 3.J.154.236; 3.J.154.237; 3.J.154.238;3.J.154.239; 3.J.154.154; 3.J.154.157; 3.J.154.166; 3.J.154.169;3.J.154.172; 3.J.154.175; 3.J.154.240; 3.J.154.244; 3.J.157.228;3.J.157.229; 3.J.157.230; 3.J.157.231; 3.J.157.236; 3.J.157.237;3.J.157.238; 3.J.157.239; 3.J.157.154; 3.J.157.157; 3.J.157.166;3.J.157.169; 3.J.157.172; 3.J.157.175; 3.J.157.240; 3.J.157.244;3.J.166.228; 3.J.166.229; 3.J.166.230; 3.J.166.231; 3.J.166.236;3.J.166.237; 3.J.166.238; 3.J.166.239; 3.J.166.154; 3.J.166.157;3.J.166.166; 3.J.166.169; 3.J.166.172; 3.J.166.175; 3.J.166.240;3.J.166.244; 3.J.169.228; 3.J.169.229; 3.J.169.230; 3.J.169.231;3.J.169.236; 3.J.169.237; 3.J.169.238; 3.J.169.239; 3.J.169.154;3.J.169.157; 3.J.169.166; 3.J.169.169; 3.J.169.172; 3.J.169.175;3.J.169.240; 3.J.169.244; 3.J.172.228; 3.J.172.229; 3.J.172.230;3.J.172.231; 3.J.172.236; 3.J.172.237; 3.J.172.238; 3.J.172.239;3.J.172.154; 3.J.172.157; 3.J.172.166; 3.J.172.169; 3.J.172.172;3.J.172.175; 3.J.172.240; 3.J.172.244; 3.J.175.228; 3.J.175.229;3.J.175.230; 3.J.175.231; 3.J.175.236; 3.J.175.237; 3.J.175.238;3.J.175.239; 3.J.175.154; 3.J.175.157; 3.J.175.166; 3.J.175.169;3.J.175.172; 3.J.175.175; 3.J.175.240; 3.J.175.244; 3.J.240.228;3.J.240.229; 3.J.240.230; 3.J.240.231; 3.J.240.236; 3.J.240.237;3.J.240.238; 3.J.240.239; 3.J.240.154; 3.J.240.157; 3.J.240.166;3.J.240.169; 3.J.240.172; 3.J.240.175; 3.J.240.240; 3.J.240.244;3.J.244.228; 3.J.244.229; 3.J.244.230; 3.J.244.231; 3.J.244.236;3.J.244.237; 3.J.244.238; 3.J.244.239; 3.J.244.154; 3.J.244.157;3.J.244.166; 3.J.244.169; 3.J.244.172; 3.J.244.175; 3.J.244.240;3.J.244.244; Prodrugs of 3.L 3.L.228.228; 3.L.228.229; 3.L.228.230;3.L.228.231; 3.L.228.236; 3.L.228.237; 3.L.228.238; 3.L.228.239;3.L.228.154; 3.L.228.157; 3.L.228.166; 3.L.228.169; 3.L.228.172;3.L.228.175; 3.L.228.240; 3.L.228.244; 3.L.229.228; 3.L.229.229;3.L.229.230; 3.L.229.231; 3.L.229.236; 3.L.229.237; 3.L.229.238;3.L.229.239; 3.L.229.154; 3.L.229.157; 3.L.229.166; 3.L.229.169;3.L.229.172; 3.L.229.175; 3.L.229.240; 3.L.229.244; 3.L.230.228;3.L.230.229; 3.L.230.230; 3.L.230.231; 3.L.230.236; 3.L.230.237;3.L.230.238; 3.L.230.239; 3.L.230.154; 3.L.230.157; 3.L.230.166;3.L.230.169; 3.L.230.172; 3.L.230.175; 3.L.230.240; 3.L.230.244;3.L.231.228; 3.L.231.229; 3.L.231.230; 3.L.231.231; 3.L.231.236;3.L.231.237; 3.L.231.238; 3.L.231.239; 3.L.231.154; 3.L.231.157;3.L.231.166; 3.L.231.169; 3.L.231.172; 3.L.231.175; 3.L.231.240;3.L.231.244; 3.L.236.228; 3.L.236.229; 3.L.236.230; 3.L.236.231;3.L.236.236; 3.L.236.237; 3.L.236.238; 3.L.236.239; 3.L.236.154;3.L.236.157; 3.L.236.166; 3.L.236.169; 3.L.236.172; 3.L.236.175;3.L.236.240; 3.L.236.244; 3.L.237.228; 3.L.237.229; 3.L.237.230;3.L.237.231; 3.L.237.236; 3.L.237.237; 3.L.237.238; 3.L.237.239;3.L.237.154; 3.L.237.157; 3.L.237.166; 3.L.237.169; 3.L.237.172;3.L.237.175; 3.L.237.240; 3.L.237.244; 3.L.238.228; 3.L.238.229;3.L.238.230; 3.L.238.231; 3.L.238.236; 3.L.238.237; 3.L.238.238;3.L.238.239; 3.L.238.154; 3.L.238.157; 3.L.238.166; 3.L.238.169;3.L.238.172; 3.L.238.175; 3.L.238.240; 3.L.238.244; 3.L.239.228;3.L.239.229; 3.L.239.230; 3.L.239.231; 3.L.239.236; 3.L.239.237;3.L.239.238; 3.L.239.239; 3.L.239.154; 3.L.239.157; 3.L.239.166;3.L.239.169; 3.L.239.172; 3.L.239.175; 3.L.239.240; 3.L.239.244;3.L.154.228; 3.L.154.229; 3.L.154.230; 3.L.154.231; 3.L.154.236;3.L.154.237; 3.L.154.238; 3.L.154.239; 3.L.154.154; 3.L.154.157;3.L.154.166; 3.L.154.169; 3.L.154.172; 3.L.154.175; 3.L.154.240;3.L.154.244; 3.L.157.228; 3.L.157.229; 3.L.157.230; 3.L.157.231;3.L.157.236; 3.L.157.237; 3.L.157.238; 3.L.157.239; 3.L.157.154;3.L.157.157; 3.L.157.166; 3.L.157.169; 3.L.157.172; 3.L.157.175;3.L.157.240; 3.L.157.244; 3.L.166.228; 3.L.166.229; 3.L.166.230;3.L.166.231; 3.L.166.236; 3.L.166.237; 3.L.166.238; 3.L.166.239;3.L.166.154; 3.L.166.157; 3.L.166.166; 3.L.166.169; 3.L.166.172;3.L.166.175; 3.L.166.240; 3.L.166.244; 3.L.169.228; 3.L.169.229;3.L.169.230; 3.L.169.231; 3.L.169.236; 3.L.169.237; 3.L.169.238;3.L.169.239; 3.L.169.154; 3.L.169.157; 3.L.169.166; 3.L.169.169;3.L.169.172; 3.L.169.175; 3.L.169.240; 3.L.169.244; 3.L.172.228;3.L.172.229; 3.L.172.230; 3.L.172.231; 3.L.172.236; 3.L.172.237;3.L.172.238; 3.L.172.239; 3.L.172.154; 3.L.172.157; 3.L.172.166;3.L.172.169; 3.L.172.172; 3.L.172.175; 3.L.172.240; 3.L.172.244;3.L.175.228; 3.L.175.229; 3.L.175.230; 3.L.175.231; 3.L.175.236;3.L.175.237; 3.L.175.238; 3.L.175.239; 3.L.175.154; 3.L.175.157;3.L.175.166; 3.L.175.169; 3.L.175.172; 3.L.175.175; 3.L.175.240;3.L.175.244; 3.L.240.228; 3.L.240.229; 3.L.240.230; 3.L.240.231;3.L.240.236; 3.L.240.237; 3.L.240.238; 3.L.240.239; 3.L.240.154;3.L.240.157; 3.L.240.166; 3.L.240.169; 3.L.240.172; 3.L.240.175;3.L.240.240; 3.L.240.244; 3.L.244.228; 3.L.244.229; 3.L.244.230;3.L.244.231; 3.L.244.236; 3.L.244.237; 3.L.244.238; 3.L.244.239;3.L.244.154; 3.L.244.157; 3.L.244.166; 3.L.244.169; 3.L.244.172;3.L.244.175; 3.L.244.240; 3.L.244.244; Prodrugs of 3.O 3.O.228.228;3.O.228.229; 3.O.228.230; 3.O.228.231; 3.O.228.236; 3.O.228.237;3.O.228.238; 3.O.228.239; 3.O.228.154; 3.O.228.157; 3.O.228.166;3.O.228.169; 3.O.228.172; 3.O.228.175; 3.O.228.240; 3.O.228.244;3.O.229.228; 3.O.229.229; 3.O.229.230; 3.O.229.231; 3.O.229.236;3.O.229.237; 3.O.229.238; 3.O.229.239; 3.O.229.154; 3.O.229.157;3.O.229.166; 3.O.229.169; 3.O.229.172; 3.O.229.175; 3.O.229.240;3.O.229.244; 3.O.230.228; 3.O.230.229; 3.O.230.230; 3.O.230.231;3.O.230.236; 3.O.230.237; 3.O.230.238; 3.O.230.239; 3.O.230.154;3.O.230.157; 3.O.230.166; 3.O.230.169; 3.O.230.172; 3.O.230.175;3.O.230.240; 3.O.230.244; 3.O.231.228; 3.O.231.229; 3.O.231.230;3.O.231.231; 3.O.231.236; 3.O.231.237; 3.O.231.238; 3.O.231.239;3.O.231.154; 3.O.231.157; 3.O.231.166; 3.O.231.169; 3.O.231.172;3.O.231.175; 3.O.231.240; 3.O.231.244; 3.O.236.228; 3.O.236.229;3.O.236.230; 3.O.236.231; 3.O.236.236; 3.O.236.237; 3.O.236.238;3.O.236.239; 3.O.236.154; 3.O.236.157; 3.O.236.166; 3.O.236.169;3.O.236.172; 3.O.236.175; 3.O.236.240; 3.O.236.244; 3.O.237.228;3.O.237.229; 3.O.237.230; 3.O.237.231; 3.O.237.236; 3.O.237.237;3.O.237.238; 3.O.237.239; 3.O.237.154; 3.O.237.157; 3.O.237.166;3.O.237.169; 3.O.237.172; 3.O.237.175; 3.O.237.240; 3.O.237.244;3.O.238.228; 3.O.238.229; 3.O.238.230; 3.O.238.231; 3.O.238.236;3.O.238.237; 3.O.238.238; 3.O.238.239; 3.O.238.154; 3.O.238.157;3.O.238.166; 3.O.238.169; 3.O.238.172; 3.O.238.175; 3.O.238.240;3.O.238.244; 3.O.239.228; 3.O.239.229; 3.O.239.230; 3.O.239.231;3.O.239.236; 3.O.239.237; 3.O.239.238; 3.O.239.239; 3.O.239.154;3.O.239.157; 3.O.239.166; 3.O.239.169; 3.O.239.172; 3.O.239.175;3.O.239.240; 3.O.239.244; 3.O.154.228; 3.O.154.229; 3.O.154.230;3.O.154.231; 3.O.154.236; 3.O.154.237; 3.O.154.238; 3.O.154.239;3.O.154.154; 3.O.154.157; 3.O.154.166; 3.O.154.169; 3.O.154.172;3.O.154.175; 3.O.154.240; 3.O.154.244; 3.O.157.228; 3.O.157.229;3.O.157.230; 3.O.157.231; 3.O.157.236; 3.O.157.237; 3.O.157.238;3.O.157.239; 3.O.157.154; 3.O.157.157; 3.O.157.166; 3.O.157.169;3.O.157.172; 3.O.157.175; 3.O.157.240; 3.O.157.244; 3.O.166.228;3.O.166.229; 3.O.166.230; 3.O.166.231; 3.O.166.236; 3.O.166.237;3.O.166.238; 3.O.166.239; 3.O.166.154; 3.O.166.157; 3.O.166.166;3.O.166.169; 3.O.166.172; 3.O.166.175; 3.O.166.240; 3.O.166.244;3.O.169.228; 3.O.169.229; 3.O.169.230; 3.O.169.231; 3.O.169.236;3.O.169.237; 3.O.169.238; 3.O.169.239; 3.O.169.154; 3.O.169.157;3.O.169.166; 3.O.169.169; 3.O.169.172; 3.O.169.175; 3.O.169.240;3.O.169.244; 3.O.172.228; 3.O.172.229; 3.O.172.230; 3.O.172.231;3.O.172.236; 3.O.172.237; 3.O.172.238; 3.O.172.239; 3.O.172.154;3.O.172.157; 3.O.172.166; 3.O.172.169; 3.O.172.172; 3.O.172.175;3.O.172.240; 3.O.172.244; 3.O.175.228; 3.O.175.229; 3.O.175.230;3.O.175.231; 3.O.175.236; 3.O.175.237; 3.O.175.238; 3.O.175.239;3.O.175.154; 3.O.175.157; 3.O.175.166; 3.O.175.169; 3.O.175.172;3.O.175.175; 3.O.175.240; 3.O.175.244; 3.O.240.228; 3.O.240.229;3.O.240.230; 3.O.240.231; 3.O.240.236; 3.O.240.237; 3.O.240.238;3.O.240.239; 3.O.240.154; 3.O.240.157; 3.O.240.166; 3.O.240.169;3.O.240.172; 3.O.240.175; 3.O.240.240; 3.O.240.244; 3.O.244.228;3.O.244.229; 3.O.244.230; 3.O.244.231; 3.O.244.236; 3.O.244.237;3.O.244.238; 3.O.244.239; 3.O.244.154; 3.O.244.157; 3.O.244.166;3.O.244.169; 3.O.244.172; 3.O.244.175; 3.O.244.240; 3.O.244.244;Prodrugs of 3.P 3.P.228.228; 3.P.228.229; 3.P.228.230; 3.P.228.231;3.P.228.236; 3.P.228.237; 3.P.228.238; 3.P.228.239; 3.P.228.154;3.P.228.157; 3.P.228.166; 3.P.228.169; 3.P.228.172; 3.P.228.175;3.P.228.240; 3.P.228.244; 3.P.229.228; 3.P.229.229; 3.P.229.230;3.P.229.231; 3.P.229.236; 3.P.229.237; 3.P.229.238; 3.P.229.239;3.P.229.154; 3.P.229.157; 3.P.229.166; 3.P.229.169; 3.P.229.172;3.P.229.175; 3.P.229.240; 3.P.229.244; 3.P.230.228; 3.P.230.229;3.P.230.230; 3.P.230.231; 3.P.230.236; 3.P.230.237; 3.P.230.238;3.P.230.239; 3.P.230.154; 3.P.230.157; 3.P.230.166; 3.P.230.169;3.P.230.172; 3.P.230.175; 3.P.230.240; 3.P.230.244; 3.P.231.228;3.P.231.229; 3.P.231.230; 3.P.231.231; 3.P.231.236; 3.P.231.237;3.P.231.238; 3.P.231.239; 3.P.231.154; 3.P.231.157; 3.P.231.166;3.P.231.169; 3.P.231.172; 3.P.231.175; 3.P.231.240; 3.P.231.244;3.P.236.228; 3.P.236.229; 3.P.236.230; 3.P.236.231; 3.P.236.236;3.P.236.237; 3.P.236.238; 3.P.236.239; 3.P.236.154; 3.P.236.157;3.P.236.166; 3.P.236.169; 3.P.236.172; 3.P.236.175; 3.P.236.240;3.P.236.244; 3.P.237.228; 3.P.237.229; 3.P.237.230; 3.P.237.231;3.P.237.236; 3.P.237.237; 3.P.237.238; 3.P.237.239; 3.P.237.154;3.P.237.157; 3.P.237.166; 3.P.237.169; 3.P.237.172; 3.P.237.175;3.P.237.240; 3.P.237.244; 3.P.238.228; 3.P.238.229; 3.P.238.230;3.P.238.231; 3.P.238.236; 3.P.238.237; 3.P.238.238; 3.P.238.239;3.P.238.154; 3.P.238.157; 3.P.238.166; 3.P.238.169; 3.P.238.172;3.P.238.175; 3.P.238.240; 3.P.238.244; 3.P.239.228; 3.P.239.229;3.P.239.230; 3.P.239.231; 3.P.239.236; 3.P.239.237; 3.P.239.238;3.P.239.239; 3.P.239.154; 3.P.239.157; 3.P.239.166; 3.P.239.169;3.P.239.172; 3.P.239.175; 3.P.239.240; 3.P.239.244; 3.P.154.228;3.P.154.229; 3.P.154.230; 3.P.154.231; 3.P.154.236; 3.P.154.237;3.P.154.238; 3.P.154.239; 3.P.154.154; 3.P.154.157; 3.P.154.166;3.P.154.169; 3.P.154.172; 3.P.154.175; 3.P.154.240; 3.P.154.244;3.P.157.228; 3.P.157.229; 3.P.157.230; 3.P.157.231; 3.P.157.236;3.P.157.237; 3.P.157.238; 3.P.157.239; 3.P.157.154; 3.P.157.157;3.P.157.166; 3.P.157.169; 3.P.157.172; 3.P.157.175; 3.P.157.240;3.P.157.244; 3.P.166.228; 3.P.166.229; 3.P.166.230; 3.P.166.231;3.P.166.236; 3.P.166.237; 3.P.166.238; 3.P.166.239; 3.P.166.154;3.P.166.157; 3.P.166.166; 3.P.166.169; 3.P.166.172; 3.P.166.175;3.P.166.240; 3.P.166.244; 3.P.169.228; 3.P.169.229; 3.P.169.230;3.P.169.231; 3.P.169.236; 3.P.169.237; 3.P.169.238; 3.P.169.239;3.P.169.154; 3.P.169.157; 3.P.169.166; 3.P.169.169; 3.P.169.172;3.P.169.175; 3.P.169.240; 3.P.169.244; 3.P.172.228; 3.P.172.229;3.P.172.230; 3.P.172.231; 3.P.172.236; 3.P.172.237; 3.P.172.238;3.P.172.239; 3.P.172.154; 3.P.172.157; 3.P.172.166; 3.P.172.169;3.P.172.172; 3.P.172.175; 3.P.172.240; 3.P.172.244; 3.P.175.228;3.P.175.229; 3.P.175.230; 3.P.175.231; 3.P.175.236; 3.P.175.237;3.P.175.238; 3.P.175.239; 3.P.175.154; 3.P.175.157; 3.P.175.166;3.P.175.169; 3.P.175.172; 3.P.175.175; 3.P.175.240; 3.P.175.244;3.P.240.228; 3.P.240.229; 3.P.240.230; 3.P.240.231; 3.P.240.236;3.P.240.237; 3.P.240.238; 3.P.240.239; 3.P.240.154; 3.P.240.157;3.P.240.166; 3.P.240.169; 3.P.240.172; 3.P.240.175; 3.P.240.240;3.P.240.244; 3.P.244.228; 3.P.244.229; 3.P.244.230; 3.P.244.231;3.P.244.236; 3.P.244.237; 3.P.244.238; 3.P.244.239; 3.P.244.154;3.P.244.157; 3.P.244.166; 3.P.244.169; 3.P.244.172; 3.P.244.175;3.P.244.240; 3.P.244.244; Prodrugs of 3.U 3.U.228.228; 3.U.228.229;3.U.228.230; 3.U.228.231; 3.U.228.236; 3.U.228.237; 3.U.228.238;3.U.228.239; 3.U.228.154; 3.U.228.157; 3.U.228.166; 3.U.228.169;3.U.228.172; 3.U.228.175; 3.U.228.240; 3.U.228.244; 3.U.229.228;3.U.229.229; 3.U.229.230; 3.U.229.231; 3.U.229.236; 3.U.229.237;3.U.229.238; 3.U.229.239; 3.U.229.154; 3.U.229.157; 3.U.229.166;3.U.229.169; 3.U.229.172; 3.U.229.175; 3.U.229.240; 3.U.229.244;3.U.230.228; 3.U.230.229; 3.U.230.230; 3.U.230.231; 3.U.230.236;3.U.230.237; 3.U.230.238; 3.U.230.239; 3.U.230.154; 3.U.230.157;3.U.230.166; 3.U.230.169; 3.U.230.172; 3.U.230.175; 3.U.230.240;3.U.230.244; 3.U.231.228; 3.U.231.229; 3.U.231.230; 3.U.231.231;3.U.231.236; 3.U.231.237; 3.U.231.238; 3.U.231.239; 3.U.231.154;3.U.231.157; 3.U.231.166; 3.U.231.169; 3.U.231.172; 3.U.231.175;3.U.231.240; 3.U.231.244; 3.U.236.228; 3.U.236.229; 3.U.236.230;3.U.236.231; 3.U.236.236; 3.U.236.237; 3.U.236.238; 3.U.236.239;3.U.236.154; 3.U.236.157; 3.U.236.166; 3.U.236.169; 3.U.236.172;3.U.236.175; 3.U.236.240; 3.U.236.244; 3.U.237.228; 3.U.237.229;3.U.237.230; 3.U.237.231; 3.U.237.236; 3.U.237.237; 3.U.237.238;3.U.237.239; 3.U.237.154; 3.U.237.157; 3.U.237.166; 3.U.237.169;3.U.237.172; 3.U.237.175; 3.U.237.240; 3.U.237.244; 3.U.238.228;3.U.238.229; 3.U.238.230; 3.U.238.231; 3.U.238.236; 3.U.238.237;3.U.238.238; 3.U.238.239; 3.U.238.154; 3.U.238.157; 3.U.238.166;3.U.238.169; 3.U.238.172; 3.U.238.175; 3.U.238.240; 3.U.238.244;3.U.239.228; 3.U.239.229; 3.U.239.230; 3.U.239.231; 3.U.239.236;3.U.239.237; 3.U.239.238; 3.U.239.239; 3.U.239.154; 3.U.239.157;3.U.239.166; 3.U.239.169; 3.U.239.172; 3.U.239.175; 3.U.239.240;3.U.239.244; 3.U.154.228; 3.U.154.229; 3.U.154.230; 3.U.154.231;3.U.154.236; 3.U.154.237; 3.U.154.238; 3.U.154.239; 3.U.154.154;3.U.154.157; 3.U.154.166; 3.U.154.169; 3.U.154.172; 3.U.154.175;3.U.154.240; 3.U.154.244; 3.U.157.228; 3.U.157.229; 3.U.157.230;3.U.157.231; 3.U.157.236; 3.U.157.237; 3.U.157.238; 3.U.157.239;3.U.157.154; 3.U.157.157; 3.U.157.166; 3.U.157.169; 3.U.157.172;3.U.157.175; 3.U.157.240; 3.U.157.244; 3.U.166.228; 3.U.166.229;3.U.166.230; 3.U.166.231; 3.U.166.236; 3.U.166.237; 3.U.166.238;3.U.166.239; 3.U.166.154; 3.U.166.157; 3.U.166.166; 3.U.166.169;3.U.166.172; 3.U.166.175; 3.U.166.240; 3.U.166.244; 3.U.169.228;3.U.169.229; 3.U.169.230; 3.U.169.231; 3.U.169.236; 3.U.169.237;3.U.169.238; 3.U.169.239; 3.U.169.154; 3.U.169.157; 3.U.169.166;3.U.169.169; 3.U.169.172; 3.U.169.175; 3.U.169.240; 3.U.169.244;3.U.172.228; 3.U.172.229; 3.U.172.230; 3.U.172.231; 3.U.172.236;3.U.172.237; 3.U.172.238; 3.U.172.239; 3.U.172.154; 3.U.172.157;3.U.172.166; 3.U.172.169; 3.U.172.172; 3.U.172.175; 3.U.172.240;3.U.172.244; 3.U.175.228; 3.U.175.229; 3.U.175.230; 3.U.175.231;3.U.175.236; 3.U.175.237; 3.U.175.238; 3.U.175.239; 3.U.175.154;3.U.175.157; 3.U.175.166; 3.U.175.169; 3.U.175.172; 3.U.175.175;3.U.175.240; 3.U.175.244; 3.U.240.228; 3.U.240.229; 3.U.240.230;3.U.240.231; 3.U.240.236; 3.U.240.237; 3.U.240.238; 3.U.240.239;3.U.240.154; 3.U.240.157; 3.U.240.166; 3.U.240.169; 3.U.240.172;3.U.240.175; 3.U.240.240; 3.U.240.244; 3.U.244.228; 3.U.244.229;3.U.244.230; 3.U.244.231; 3.U.244.236; 3.U.244.237; 3.U.244.238;3.U.244.239; 3.U.244.154; 3.U.244.157; 3.U.244.166; 3.U.244.169;3.U.244.172; 3.U.244.175; 3.U.244.240; 3.U.244.244; Prodrugs of 3.W3.W.228.228; 3.W.228.229; 3.W.228.230; 3.W.228.231; 3.W.228.236;3.W.228.237; 3.W.228.238; 3.W.228.239; 3.W.228.154; 3.W.228.157;3.W.228.166; 3.W.228.169; 3.W.228.172; 3.W.228.175; 3.W.228.240;3.W.228.244; 3.W.229.228; 3.W.229.229; 3.W.229.230; 3.W.229.231;3.W.229.236; 3.W.229.237; 3.W.229.238; 3.W.229.239; 3.W.229.154;3.W.229.157; 3.W.229.166; 3.W.229.169; 3.W.229.172; 3.W.229.175;3.W.229.240; 3.W.229.244; 3.W.230.228; 3.W.230.229; 3.W.230.230;3.W.230.231; 3.W.230.236; 3.W.230.237; 3.W.230.238; 3.W.230.239;3.W.230.154; 3.W.230.157; 3.W.230.166; 3.W.230.169; 3.W.230.172;3.W.230.175; 3.W.230.240; 3.W.230.244; 3.W.231.228; 3.W.231.229;3.W.231.230; 3.W.231.231; 3.W.231.236; 3.W.231.237; 3.W.231.238;3.W.231.239; 3.W.231.154; 3.W.231.157; 3.W.231.166; 3.W.231.169;3.W.231.172; 3.W.231.175; 3.W.231.240; 3.W.231.244; 3.W.236.228;3.W.236.229; 3.W.236.230; 3.W.236.231; 3.W.236.236; 3.W.236.237;3.W.236.238; 3.W.236.239; 3.W.236.154; 3.W.236.157; 3.W.236.166;3.W.236.169; 3.W.236.172; 3.W.236.175; 3.W.236.240; 3.W.236.244;3.W.237.228; 3.W.237.229; 3.W.237.230; 3.W.237.231; 3.W.237.236;3.W.237.237; 3.W.237.238; 3.W.237.239; 3.W.237.154; 3.W.237.157;3.W.237.166; 3.W.237.169; 3.W.237.172; 3.W.237.175; 3.W.237.240;3.W.237.244; 3.W.238.228; 3.W.238.229; 3.W.238.230; 3.W.238.231;3.W.238.236; 3.W.238.237; 3.W.238.238; 3.W.238.239; 3.W.238.154;3.W.238.157; 3.W.238.166; 3.W.238.169; 3.W.238.172; 3.W.238.175;3.W.238.240; 3.W.238.244; 3.W.239.228; 3.W.239.229; 3.W.239.230;3.W.239.231; 3.W.239.236; 3.W.239.237; 3.W.239.238; 3.W.239.239;3.W.239.154; 3.W.239.157; 3.W.239.166; 3.W.239.169; 3.W.239.172;3.W.239.175; 3.W.239.240; 3.W.239.244; 3.W.154.228; 3.W.154.229;3.W.154.230; 3.W.154.231; 3.W.154.236; 3.W.154.237; 3.W.154.238;3.W.154.239; 3.W.154.154; 3.W.154.157; 3.W.154.166; 3.W.154.169;3.W.154.172; 3.W.154.175; 3.W.154.240; 3.W.154.244; 3.W.157.228;3.W.157.229; 3.W.157.230; 3.W.157.231; 3.W.157.236; 3.W.157.237;3.W.157.238; 3.W.157.239; 3.W.157.154; 3.W.157.157; 3.W.157.166;3.W.157.169; 3.W.157.172; 3.W.157.175; 3.W.157.240; 3.W.157.244;3.W.166.228; 3.W.166.229; 3.W.166.230; 3.W.166.231; 3.W.166.236;3.W.166.237; 3.W.166.238; 3.W.166.239; 3.W.166.154; 3.W.166.157;3.W.166.166; 3.W.166.169; 3.W.166.172; 3.W.166.175; 3.W.166.240;3.W.166.244; 3.W.169.228; 3.W.169.229; 3.W.169.230; 3.W.169.231;3.W.169.236; 3.W.169.237; 3.W.169.238; 3.W.169.239; 3.W.169.154;3.W.169.157; 3.W.169.166; 3.W.169.169; 3.W.169.172; 3.W.169.175;3.W.169.240; 3.W.169.244; 3.W.172.228; 3.W.172.229; 3.W.172.230;3.W.172.231; 3.W.172.236; 3.W.172.237; 3.W.172.238; 3.W.172.239;3.W.172.154; 3.W.172.157; 3.W.172.166; 3.W.172.169; 3.W.172.172;3.W.172.175; 3.W.172.240; 3.W.172.244; 3.W.175.228; 3.W.175.229;3.W.175.230; 3.W.175.231; 3.W.175.236; 3.W.175.237; 3.W.175.238;3.W.175.239; 3.W.175.154; 3.W.175.157; 3.W.175.166; 3.W.175.169;3.W.175.172; 3.W.175.175; 3.W.175.240; 3.W.175.244; 3.W.240.228;3.W.240.229; 3.W.240.230; 3.W.240.231; 3.W.240.236; 3.W.240.237;3.W.240.238; 3.W.240.239; 3.W.240.154; 3.W.240.157; 3.W.240.166;3.W.240.169; 3.W.240.172; 3.W.240.175; 3.W.240.240; 3.W.240.244;3.W.244.228; 3.W.244.229; 3.W.244.230; 3.W.244.231; 3.W.244.236;3.W.244.237; 3.W.244.238; 3.W.244.239; 3.W.244.154; 3.W.244.157;3.W.244.166; 3.W.244.169; 3.W.244.172; 3.W.244.175; 3.W.244.240;3.W.244.244; Prodrugs of 3.Y 3.Y.228.228; 3.Y.228.229; 3.Y.228.230;3.Y.228.231; 3.Y.228.236; 3.Y.228.237; 3.Y.228.238; 3.Y.228.239;3.Y.228.154; 3.Y.228.157; 3.Y.228.166; 3.Y.228.169; 3.Y.228.172;3.Y.228.175; 3.Y.228.240; 3.Y.228.244; 3.Y.229.228; 3.Y.229.229;3.Y.229.230; 3.Y.229.231; 3.Y.229.236; 3.Y.229.237; 3.Y.229.238;3.Y.229.239; 3.Y.229.154; 3.Y.229.157; 3.Y.229.166; 3.Y.229.169;3.Y.229.172; 3.Y.229.175; 3.Y.229.240; 3.Y.229.244; 3.Y.230.228;3.Y.230.229; 3.Y.230.230; 3.Y.230.231; 3.Y.230.236; 3.Y.230.237;3.Y.230.238; 3.Y.230.239; 3.Y.230.154; 3.Y.230.157; 3.Y.230.166;3.Y.230.169; 3.Y.230.172; 3.Y.230.175; 3.Y.230.240; 3.Y.230.244;3.Y.231.228; 3.Y.231.229; 3.Y.231.230; 3.Y.231.231; 3.Y.231.236;3.Y.231.237; 3.Y.231.238; 3.Y.231.239; 3.Y.231.154; 3.Y.231.157;3.Y.231.166; 3.Y.231.169; 3.Y.231.172; 3.Y.231.175; 3.Y.231.240;3.Y.231.244; 3.Y.236.228; 3.Y.236.229; 3.Y.236.230; 3.Y.236.231;3.Y.236.236; 3.Y.236.237; 3.Y.236.238; 3.Y.236.239; 3.Y.236.154;3.Y.236.157; 3.Y.236.166; 3.Y.236.169; 3.Y.236.172; 3.Y.236.175;3.Y.236.240; 3.Y.236.244; 3.Y.237.228; 3.Y.237.229; 3.Y.237.230;3.Y.237.231; 3.Y.237.236; 3.Y.237.237; 3.Y.237.238; 3.Y.237.239;3.Y.237.154; 3.Y.237.157; 3.Y.237.166; 3.Y.237.169; 3.Y.237.172;3.Y.237.175; 3.Y.237.240; 3.Y.237.244; 3.Y.238.228; 3.Y.238.229;3.Y.238.230; 3.Y.238.231; 3.Y.238.236; 3.Y.238.237; 3.Y.238.238;3.Y.238.239; 3.Y.238.154; 3.Y.238.157; 3.Y.238.166; 3.Y.238.169;3.Y.238.172; 3.Y.238.175; 3.Y.238.240; 3.Y.238.244; 3.Y.239.228;3.Y.239.229; 3.Y.239.230; 3.Y.239.231; 3.Y.239.236; 3.Y.239.237;3.Y.239.238; 3.Y.239.239; 3.Y.239.154; 3.Y.239.157; 3.Y.239.166;3.Y.239.169; 3.Y.239.172; 3.Y.239.175; 3.Y.239.240; 3.Y.239.244;3.Y.154.228; 3.Y.154.229; 3.Y.154.230; 3.Y.154.231; 3.Y.154.236;3.Y.154.237; 3.Y.154.238; 3.Y.154.239; 3.Y.154.154; 3.Y.154.157;3.Y.154.166; 3.Y.154.169; 3.Y.154.172; 3.Y.154.175; 3.Y.154.240;3.Y.154.244; 3.Y.157.228; 3.Y.157.229; 3.Y.157.230; 3.Y.157.231;3.Y.157.236; 3.Y.157.237; 3.Y.157.238; 3.Y.157.239; 3.Y.157.154;3.Y.157.157; 3.Y.157.166; 3.Y.157.169; 3.Y.157.172; 3.Y.157.175;3.Y.157.240; 3.Y.157.244; 3.Y.166.228; 3.Y.166.229; 3.Y.166.230;3.Y.166.231; 3.Y.166.236; 3.Y.166.237; 3.Y.166.238; 3.Y.166.239;3.Y.166.154; 3.Y.166.157; 3.Y.166.166; 3.Y.166.169; 3.Y.166.172;3.Y.166.175; 3.Y.166.240; 3.Y.166.244; 3.Y.169.228; 3.Y.169.229;3.Y.169.230; 3.Y.169.231; 3.Y.169.236; 3.Y.169.237; 3.Y.169.238;3.Y.169.239; 3.Y.169.154; 3.Y.169.157; 3.Y.169.166; 3.Y.169.169;3.Y.169.172; 3.Y.169.175; 3.Y.169.240; 3.Y.169.244; 3.Y.172.228;3.Y.172.229; 3.Y.172.230; 3.Y.172.231; 3.Y.172.236; 3.Y.172.237;3.Y.172.238; 3.Y.172.239; 3.Y.172.154; 3.Y.172.157; 3.Y.172.166;3.Y.172.169; 3.Y.172.172; 3.Y.172.175; 3.Y.172.240; 3.Y.172.244;3.Y.175.228; 3.Y.175.229; 3.Y.175.230; 3.Y.175.231; 3.Y.175.236;3.Y.175.237; 3.Y.175.238; 3.Y.175.239; 3.Y.175.154; 3.Y.175.157;3.Y.175.166; 3.Y.175.169; 3.Y.175.172; 3.Y.175.175; 3.Y.175.240;3.Y.175.244; 3.Y.240.228; 3.Y.240.229; 3.Y.240.230; 3.Y.240.231;3.Y.240.236; 3.Y.240.237; 3.Y.240.238; 3.Y.240.239; 3.Y.240.154;3.Y.240.157; 3.Y.240.166; 3.Y.240.169; 3.Y.240.172; 3.Y.240.175;3.Y.240.240; 3.Y.240.244; 3.Y.244.228; 3.Y.244.229; 3.Y.244.230;3.Y.244.231; 3.Y.244.236; 3.Y.244.237; 3.Y.244.238; 3.Y.244.239;3.Y.244.154; 3.Y.244.157; 3.Y.244.166; 3.Y.244.169; 3.Y.244.172;3.Y.244.175; 3.Y.244.240; 3.Y.244.244; Prodrugs of 4.B 4.B.228.228;4.B.228.229; 4.B.228.230; 4.B.228.231; 4.B.228.236; 4.B.228.237;4.B.228.238; 4.B.228.239; 4.B.228.154; 4.B.228.157; 4.B.228.166;4.B.228.169; 4.B.228.172; 4.B.228.175; 4.B.228.240; 4.B.228.244;4.B.229.228; 4.B.229.229; 4.B.229.230; 4.B.229.231; 4.B.229.236;4.B.229.237; 4.B.229.238; 4.B.229.239; 4.B.229.154; 4.B.229.157;4.B.229.166; 4.B.229.169; 4.B.229.172; 4.B.229.175; 4.B.229.240;4.B.229.244; 4.B.230.228; 4.B.230.229; 4.B.230.230; 4.B.230.231;4.B.230.236; 4.B.230.237; 4.B.230.238; 4.B.230.239; 4.B.230.154;4.B.230.157; 4.B.230.166; 4.B.230.169; 4.B.230.172; 4.B.230.175;4.B.230.240; 4.B.230.244; 4.B.231.228; 4.B.231.229; 4.B.231.230;4.B.231.231; 4.B.231.236; 4.B.231.237; 4.B.231.238; 4.B.231.239;4.B.231.154; 4.B.231.157; 4.B.231.166; 4.B.231.169; 4.B.231.172;4.B.231.175; 4.B.231.240; 4.B.231.244; 4.B.236.228; 4.B.236.229;4.B.236.230; 4.B.236.231; 4.B.236.236; 4.B.236.237; 4.B.236.238;4.B.236.239; 4.B.236.154; 4.B.236.157; 4.B.236.166; 4.B.236.169;4.B.236.172; 4.B.236.175; 4.B.236.240; 4.B.236.244; 4.B.237.228;4.B.237.229; 4.B.237.230; 4.B.237.231; 4.B.237.236; 4.B.237.237;4.B.237.238; 4.B.237.239; 4.B.237.154; 4.B.237.157; 4.B.237.166;4.B.237.169; 4.B.237.172; 4.B.237.175; 4.B.237.240; 4.B.237.244;4.B.238.228; 4.B.238.229; 4.B.238.230; 4.B.238.231; 4.B.238.236;4.B.238.237; 4.B.238.238; 4.B.238.239; 4.B.238.154; 4.B.238.157;4.B.238.166; 4.B.238.169; 4.B.238.172; 4.B.238.175; 4.B.238.240;4.B.238.244; 4.B.239.228; 4.B.239.229; 4.B.239.230; 4.B.239.231;4.B.239.236; 4.B.239.237; 4.B.239.238; 4.B.239.239; 4.B.239.154;4.B.239.157; 4.B.239.166; 4.B.239.169; 4.B.239.172; 4.B.239.175;4.B.239.240; 4.B.239.244; 4.B.154.228; 4.B.154.229; 4.B.154.230;4.B.154.231; 4.B.154.236; 4.B.154.237; 4.B.154.238; 4.B.154.239;4.B.154.154; 4.B.154.157; 4.B.154.166; 4.B.154.169; 4.B.154.172;4.B.154.175; 4.B.154.240; 4.B.154.244; 4.B.157.228; 4.B.157.229;4.B.157.230; 4.B.157.231; 4.B.157.236; 4.B.157.237; 4.B.157.238;4.B.157.239; 4.B.157.154; 4.B.157.157; 4.B.157.166; 4.B.157.169;4.B.157.172; 4.B.157.175; 4.B.157.240; 4.B.157.244; 4.B.166.228;4.B.166.229; 4.B.166.230; 4.B.166.231; 4.B.166.236; 4.B.166.237;4.B.166.238; 4.B.166.239; 4.B.166.154; 4.B.166.157; 4.B.166.166;4.B.166.169; 4.B.166.172; 4.B.166.175; 4.B.166.240; 4.B.166.244;4.B.169.228; 4.B.169.229; 4.B.169.230; 4.B.169.231; 4.B.169.236;4.B.169.237; 4.B.169.238; 4.B.169.239; 4.B.169.154; 4.B.169.157;4.B.169.166; 4.B.169.169; 4.B.169.172; 4.B.169.175; 4.B.169.240;4.B.169.244; 4.B.172.228; 4.B.172.229; 4.B.172.230; 4.B.172.231;4.B.172.236; 4.B.172.237; 4.B.172.238; 4.B.172.239; 4.B.172.154;4.B.172.157; 4.B.172.166; 4.B.172.169; 4.B.172.172; 4.B.172.175;4.B.172.240; 4.B.172.244; 4.B.175.228; 4.B.175.229; 4.B.175.230;4.B.175.231; 4.B.175.236; 4.B.175.237; 4.B.175.238; 4.B.175.239;4.B.175.154; 4.B.175.157; 4.B.175.166; 4.B.175.169; 4.B.175.172;4.B.175.175; 4.B.175.240; 4.B.175.244; 4.B.240.228; 4.B.240.229;4.B.240.230; 4.B.240.231; 4.B.240.236; 4.B.240.237; 4.B.240.238;4.B.240.239; 4.B.240.154; 4.B.240.157; 4.B.240.166; 4.B.240.169;4.B.240.172; 4.B.240.175; 4.B.240.240; 4.B.240.244; 4.B.244.228;4.B.244.229; 4.B.244.230; 4.B.244.231; 4.B.244.236; 4.B.244.237;4.B.244.238; 4.B.244.239; 4.B.244.154; 4.B.244.157; 4.B.244.166;4.B.244.169; 4.B.244.172; 4.B.244.175; 4.B.244.240; 4.B.244.244;Prodrugs of 4.D 4.D.228.228; 4.D.228.229; 4.D.228.230; 4.D.228.231;4.D.228.236; 4.D.228.237; 4.D.228.238; 4.D.228.239; 4.D.228.154;4.D.228.157; 4.D.228.166; 4.D.228.169; 4.D.228.172; 4.D.228.175;4.D.228.240; 4.D.228.244; 4.D.229.228; 4.D.229.229; 4.D.229.230;4.D.229.231; 4.D.229.236; 4.D.229.237; 4.D.229.238; 4.D.229.239;4.D.229.154; 4.D.229.157; 4.D.229.166; 4.D.229.169; 4.D.229.172;4.D.229.175; 4.D.229.240; 4.D.229.244; 4.D.230.228; 4.D.230.229;4.D.230.230; 4.D.230.231; 4.D.230.236; 4.D.230.237; 4.D.230.238;4.D.230.239; 4.D.230.154; 4.D.230.157; 4.D.230.166; 4.D.230.169;4.D.230.172; 4.D.230.175; 4.D.230.240; 4.D.230.244; 4.D.231.228;4.D.231.229; 4.D.231.230; 4.D.231.231; 4.D.231.236; 4.D.231.237;4.D.231.238; 4.D.231.239; 4.D.231.154; 4.D.231.157; 4.D.231.166;4.D.231.169; 4.D.231.172; 4.D.231.175; 4.D.231.240; 4.D.231.244;4.D.236.228; 4.D.236.229; 4.D.236.230; 4.D.236.231; 4.D.236.236;4.D.236.237; 4.D.236.238; 4.D.236.239; 4.D.236.154; 4.D.236.157;4.D.236.166; 4.D.236.169; 4.D.236.172; 4.D.236.175; 4.D.236.240;4.D.236.244; 4.D.237.228; 4.D.237.229; 4.D.237.230; 4.D.237.231;4.D.237.236; 4.D.237.237; 4.D.237.238; 4.D.237.239; 4.D.237.154;4.D.237.157; 4.D.237.166; 4.D.237.169; 4.D.237.172; 4.D.237.175;4.D.237.240; 4.D.237.244; 4.D.238.228; 4.D.238.229; 4.D.238.230;4.D.238.231; 4.D.238.236; 4.D.238.237; 4.D.238.238; 4.D.238.239;4.D.238.154; 4.D.238.157; 4.D.238.166; 4.D.238.169; 4.D.238.172;4.D.238.175; 4.D.238.240; 4.D.238.244; 4.D.239.228; 4.D.239.229;4.D.239.230; 4.D.239.231; 4.D.239.236; 4.D.239.237; 4.D.239.238;4.D.239.239; 4.D.239.154; 4.D.239.157; 4.D.239.166; 4.D.239.169;4.D.239.172; 4.D.239.175; 4.D.239.240; 4.D.239.244; 4.D.154.228;4.D.154.229; 4.D.154.230; 4.D.154.231; 4.D.154.236; 4.D.154.237;4.D.154.238; 4.D.154.239; 4.D.154.154; 4.D.154.157; 4.D.154.166;4.D.154.169; 4.D.154.172; 4.D.154.175; 4.D.154.240; 4.D.154.244;4.D.157.228; 4.D.157.229; 4.D.157.230; 4.D.157.231; 4.D.157.236;4.D.157.237; 4.D.157.238; 4.D.157.239; 4.D.157.154; 4.D.157.157;4.D.157.166; 4.D.157.169; 4.D.157.172; 4.D.157.175; 4.D.157.240;4.D.157.244; 4.D.166.228; 4.D.166.229; 4.D.166.230; 4.D.166.231;4.D.166.236; 4.D.166.237; 4.D.166.238; 4.D.166.239; 4.D.166.154;4.D.166.157; 4.D.166.166; 4.D.166.169; 4.D.166.172; 4.D.166.175;4.D.166.240; 4.D.166.244; 4.D.169.228; 4.D.169.229; 4.D.169.230;4.D.169.231; 4.D.169.236; 4.D.169.237; 4.D.169.238; 4.D.169.239;4.D.169.154; 4.D.169.157; 4.D.169.166; 4.D.169.169; 4.D.169.172;4.D.169.175; 4.D.169.240; 4.D.169.244; 4.D.172.228; 4.D.172.229;4.D.172.230; 4.D.172.231; 4.D.172.236; 4.D.172.237; 4.D.172.238;4.D.172.239; 4.D.172.154; 4.D.172.157; 4.D.172.166; 4.D.172.169;4.D.172.172; 4.D.172.175; 4.D.172.240; 4.D.172.244; 4.D.175.228;4.D.175.229; 4.D.175.230; 4.D.175.231; 4.D.175.236; 4.D.175.237;4.D.175.238; 4.D.175.239; 4.D.175.154; 4.D.175.157; 4.D.175.166;4.D.175.169; 4.D.175.172; 4.D.175.175; 4.D.175.240; 4.D.175.244;4.D.240.228; 4.D.240.229; 4.D.240.230; 4.D.240.231; 4.D.240.236;4.D.240.237; 4.D.240.238; 4.D.240.239; 4.D.240.154; 4.D.240.157;4.D.240.166; 4.D.240.169; 4.D.240.172; 4.D.240.175; 4.D.240.240;4.D.240.244; 4.D.244.228; 4.D.244.229; 4.D.244.230; 4.D.244.231;4.D.244.236; 4.D.244.237; 4.D.244.238; 4.D.244.239; 4.D.244.154;4.D.244.157; 4.D.244.166; 4.D.244.169; 4.D.244.172; 4.D.244.175;4.D.244.240; 4.D.244.244; Prodrugs of 4.E 4.E.228.228; 4.E.228.229;4.E.228.230; 4.E.228.231; 4.E.228.236; 4.E.228.237; 4.E.228.238;4.E.228.239; 4.E.228.154; 4.E.228.157; 4.E.228.166; 4.E.228.169;4.E.228.172; 4.E.228.175; 4.E.228.240; 4.E.228.244; 4.E.229.228;4.E.229.229; 4.E.229.230; 4.E.229.231; 4.E.229.236; 4.E.229.237;4.E.229.238; 4.E.229.239; 4.E.229.154; 4.E.229.157; 4.E.229.166;4.E.229.169; 4.E.229.172; 4.E.229.175; 4.E.229.240; 4.E.229.244;4.E.230.228; 4.E.230.229; 4.E.230.230; 4.E.230.231; 4.E.230.236;4.E.230.237; 4.E.230.238; 4.E.230.239; 4.E.230.154; 4.E.230.157;4.E.230.166; 4.E.230.169; 4.E.230.172; 4.E.230.175; 4.E.230.240;4.E.230.244; 4.E.231.228; 4.E.231.229; 4.E.231.230; 4.E.231.231;4.E.231.236; 4.E.231.237; 4.E.231.238; 4.E.231.239; 4.E.231.154;4.E.231.157; 4.E.231.166; 4.E.231.169; 4.E.231.172; 4.E.231.175;4.E.231.240; 4.E.231.244; 4.E.236.228; 4.E.236.229; 4.E.236.230;4.E.236.231; 4.E.236.236; 4.E.236.237; 4.E.236.238; 4.E.236.239;4.E.236.154; 4.E.236.157; 4.E.236.166; 4.E.236.169; 4.E.236.172;4.E.236.175; 4.E.236.240; 4.E.236.244; 4.E.237.228; 4.E.237.229;4.E.237.230; 4.E.237.231; 4.E.237.236; 4.E.237.237; 4.E.237.238;4.E.237.239; 4.E.237.154; 4.E.237.157; 4.E.237.166; 4.E.237.169;4.E.237.172; 4.E.237.175; 4.E.237.240; 4.E.237.244; 4.E.238.228;4.E.238.229; 4.E.238.230; 4.E.238.231; 4.E.238.236; 4.E.238.237;4.E.238.238; 4.E.238.239; 4.E.238.154; 4.E.238.157; 4.E.238.166;4.E.238.169; 4.E.238.172; 4.E.238.175; 4.E.238.240; 4.E.238.244;4.E.239.228; 4.E.239.229; 4.E.239.230; 4.E.239.231; 4.E.239.236;4.E.239.237; 4.E.239.238; 4.E.239.239; 4.E.239.154; 4.E.239.157;4.E.239.166; 4.E.239.169; 4.E.239.172; 4.E.239.175; 4.E.239.240;4.E.239.244; 4.E.154.228; 4.E.154.229; 4.E.154.230; 4.E.154.231;4.E.154.236; 4.E.154.237; 4.E.154.238; 4.E.154.239; 4.E.154.154;4.E.154.157; 4.E.154.166; 4.E.154.169; 4.E.154.172; 4.E.154.175;4.E.154.240; 4.E.154.244; 4.E.157.228; 4.E.157.229; 4.E.157.230;4.E.157.231; 4.E.157.236; 4.E.157.237; 4.E.157.238; 4.E.157.239;4.E.157.154; 4.E.157.157; 4.E.157.166; 4.E.157.169; 4.E.157.172;4.E.157.175; 4.E.157.240; 4.E.157.244; 4.E.166.228; 4.E.166.229;4.E.166.230; 4.E.166.231; 4.E.166.236; 4.E.166.237; 4.E.166.238;4.E.166.239; 4.E.166.154; 4.E.166.157; 4.E.166.166; 4.E.166.169;4.E.166.172; 4.E.166.175; 4.E.166.240; 4.E.166.244; 4.E.169.228;4.E.169.229; 4.E.169.230; 4.E.169.231; 4.E.169.236; 4.E.169.237;4.E.169.238; 4.E.169.239; 4.E.169.154; 4.E.169.157; 4.E.169.166;4.E.169.169; 4.E.169.172; 4.E.169.175; 4.E.169.240; 4.E.169.244;4.E.172.228; 4.E.172.229; 4.E.172.230; 4.E.172.231; 4.E.172.236;4.E.172.237; 4.E.172.238; 4.E.172.239; 4.E.172.154; 4.E.172.157;4.E.172.166; 4.E.172.169; 4.E.172.172; 4.E.172.175; 4.E.172.240;4.E.172.244; 4.E.175.228; 4.E.175.229; 4.E.175.230; 4.E.175.231;4.E.175.236; 4.E.175.237; 4.E.175.238; 4.E.175.239; 4.E.175.154;4.E.175.157; 4.E.175.166; 4.E.175.169; 4.E.175.172; 4.E.175.175;4.E.175.240; 4.E.175.244; 4.E.240.228; 4.E.240.229; 4.E.240.230;4.E.240.231; 4.E.240.236; 4.E.240.237; 4.E.240.238; 4.E.240.239;4.E.240.154; 4.E.240.157; 4.E.240.166; 4.E.240.169; 4.E.240.172;4.E.240.175; 4.E.240.240; 4.E.240.244; 4.E.244.228; 4.E.244.229;4.E.244.230; 4.E.244.231; 4.E.244.236; 4.E.244.237; 4.E.244.238;4.E.244.239; 4.E.244.154; 4.E.244.157; 4.E.244.166; 4.E.244.169;4.E.244.172; 4.E.244.175; 4.E.244.240; 4.E.244.244; Prodrugs of 4.G4.G.228.228; 4.G.228.229; 4.G.228.230; 4.G.228.231; 4.G.228.236;4.G.228.237; 4.G.228.238; 4.G.228.239; 4.G.228.154; 4.G.228.157;4.G.228.166; 4.G.228.169; 4.G.228.172; 4.G.228.175; 4.G.228.240;4.G.228.244; 4.G.229.228; 4.G.229.229; 4.G.229.230; 4.G.229.231;4.G.229.236; 4.G.229.237; 4.G.229.238; 4.G.229.239; 4.G.229.154;4.G.229.157; 4.G.229.166; 4.G.229.169; 4.G.229.172; 4.G.229.175;4.G.229.240; 4.G.229.244; 4.G.230.228; 4.G.230.229; 4.G.230.230;4.G.230.231; 4.G.230.236; 4.G.230.237; 4.G.230.238; 4.G.230.239;4.G.230.154; 4.G.230.157; 4.G.230.166; 4.G.230.169; 4.G.230.172;4.G.230.175; 4.G.230.240; 4.G.230.244; 4.G.231.228; 4.G.231.229;4.G.231.230; 4.G.231.231; 4.G.231.236; 4.G.231.237; 4.G.231.238;4.G.231.239; 4.G.231.154; 4.G.231.157; 4.G.231.166; 4.G.231.169;4.G.231.172; 4.G.231.175; 4.G.231.240; 4.G.231.244; 4.G.236.228;4.G.236.229; 4.G.236.230; 4.G.236.231; 4.G.236.236; 4.G.236.237;4.G.236.238; 4.G.236.239; 4.G.236.154; 4.G.236.157; 4.G.236.166;4.G.236.169; 4.G.236.172; 4.G.236.175; 4.G.236.240; 4.G.236.244;4.G.237.228; 4.G.237.229; 4.G.237.230; 4.G.237.231; 4.G.237.236;4.G.237.237; 4.G.237.238; 4.G.237.239; 4.G.237.154; 4.G.237.157;4.G.237.166; 4.G.237.169; 4.G.237.172; 4.G.237.175; 4.G.237.240;4.G.237.244; 4.G.238.228; 4.G.238.229; 4.G.238.230; 4.G.238.231;4.G.238.236; 4.G.238.237; 4.G.238.238; 4.G.238.239; 4.G.238.154;4.G.238.157; 4.G.238.166; 4.G.238.169; 4.G.238.172; 4.G.238.175;4.G.238.240; 4.G.238.244; 4.G.239.228; 4.G.239.229; 4.G.239.230;4.G.239.231; 4.G.239.236; 4.G.239.237; 4.G.239.238; 4.G.239.239;4.G.239.154; 4.G.239.157; 4.G.239.166; 4.G.239.169; 4.G.239.172;4.G.239.175; 4.G.239.240; 4.G.239.244; 4.G.154.228; 4.G.154.229;4.G.154.230; 4.G.154.231; 4.G.154.236; 4.G.154.237; 4.G.154.238;4.G.154.239; 4.G.154.154; 4.G.154.157; 4.G.154.166; 4.G.154.169;4.G.154.172; 4.G.154.175; 4.G.154.240; 4.G.154.244; 4.G.157.228;4.G.157.229; 4.G.157.230; 4.G.157.231; 4.G.157.236; 4.G.157.237;4.G.157.238; 4.G.157.239; 4.G.157.154; 4.G.157.157; 4.G.157.166;4.G.157.169; 4.G.157.172; 4.G.157.175; 4.G.157.240; 4.G.157.244;4.G.166.228; 4.G.166.229; 4.G.166.230; 4.G.166.231; 4.G.166.236;4.G.166.237; 4.G.166.238; 4.G.166.239; 4.G.166.154; 4.G.166.157;4.G.166.166; 4.G.166.169; 4.G.166.172; 4.G.166.175; 4.G.166.240;4.G.166.244; 4.G.169.228; 4.G.169.229; 4.G.169.230; 4.G.169.231;4.G.169.236; 4.G.169.237; 4.G.169.238; 4.G.169.239; 4.G.169.154;4.G.169.157; 4.G.169.166; 4.G.169.169; 4.G.169.172; 4.G.169.175;4.G.169.240; 4.G.169.244; 4.G.172.228; 4.G.172.229; 4.G.172.230;4.G.172.231; 4.G.172.236; 4.G.172.237; 4.G.172.238; 4.G.172.239;4.G.172.154; 4.G.172.157; 4.G.172.166; 4.G.172.169; 4.G.172.172;4.G.172.175; 4.G.172.240; 4.G.172.244; 4.G.175.228; 4.G.175.229;4.G.175.230; 4.G.175.231; 4.G.175.236; 4.G.175.237; 4.G.175.238;4.G.175.239; 4.G.175.154; 4.G.175.157; 4.G.175.166; 4.G.175.169;4.G.175.172; 4.G.175.175; 4.G.175.240; 4.G.175.244; 4.G.240.228;4.G.240.229; 4.G.240.230; 4.G.240.231; 4.G.240.236; 4.G.240.237;4.G.240.238; 4.G.240.239; 4.G.240.154; 4.G.240.157; 4.G.240.166;4.G.240.169; 4.G.240.172; 4.G.240.175; 4.G.240.240; 4.G.240.244;4.G.244.228; 4.G.244.229; 4.G.244.230; 4.G.244.231; 4.G.244.236;4.G.244.237; 4.G.244.238; 4.G.244.239; 4.G.244.154; 4.G.244.157;4.G.244.166; 4.G.244.169; 4.G.244.172; 4.G.244.175; 4.G.244.240;4.G.244.244; Prodrugs of 4.I 4.I.228.228; 4.I.228.229; 4.I.228.230;4.I.228.231; 4.I.228.236; 4.I.228.237; 4.I.228.238; 4.I.228.239;4.I.228.154; 4.I.228.157; 4.I.228.166; 4.I.228.169; 4.I.228.172;4.I.228.175; 4.I.228.240; 4.I.228.244; 4.I.229.228; 4.I.229.229;4.I.229.230; 4.I.229.231; 4.I.229.236; 4.I.229.237; 4.I.229.238;4.I.229.239; 4.I.229.154; 4.I.229.157; 4.I.229.166; 4.I.229.169;4.I.229.172; 4.I.229.175; 4.I.229.240; 4.I.229.244; 4.I.230.228;4.I.230.229; 4.I.230.230; 4.I.230.231; 4.I.230.236; 4.I.230.237;4.I.230.238; 4.I.230.239; 4.I.230.154; 4.I.230.157; 4.I.230.166;4.I.230.169; 4.I.230.172; 4.I.230.175; 4.I.230.240; 4.I.230.244;4.I.231.228; 4.I.231.229; 4.I.231.230; 4.I.231.231; 4.I.231.236;4.I.231.237; 4.I.231.238; 4.I.231.239; 4.I.231.154; 4.I.231.157;4.I.231.166; 4.I.231.169; 4.I.231.172; 4.I.231.175; 4.I.231.240;4.I.231.244; 4.I.236.228; 4.I.236.229; 4.I.236.230; 4.I.236.231;4.I.236.236; 4.I.236.237; 4.I.236.238; 4.I.236.239; 4.I.236.154;4.I.236.157; 4.I.236.166; 4.I.236.169; 4.I.236.172; 4.I.236.175;4.I.236.240; 4.I.236.244; 4.I.237.228; 4.I.237.229; 4.I.237.230;4.I.237.231; 4.I.237.236; 4.I.237.237; 4.I.237.238; 4.I.237.239;4.I.237.154; 4.I.237.157; 4.I.237.166; 4.I.237.169; 4.I.237.172;4.I.237.175; 4.I.237.240; 4.I.237.244; 4.I.238.228; 4.I.238.229;4.I.238.230; 4.I.238.231; 4.I.238.236; 4.I.238.237; 4.I.238.238;4.I.238.239; 4.I.238.154; 4.I.238.157; 4.I.238.166; 4.I.238.169;4.I.238.172; 4.I.238.175; 4.I.238.240; 4.I.238.244; 4.I.239.228;4.I.239.229; 4.I.239.230; 4.I.239.231; 4.I.239.236; 4.I.239.237;4.I.239.238; 4.I.239.239; 4.I.239.154; 4.I.239.157; 4.I.239.166;4.I.239.169; 4.I.239.172; 4.I.239.175; 4.I.239.240; 4.I.239.244;4.I.154.228; 4.I.154.229; 4.I.154.230; 4.I.154.231; 4.I.154.236;4.I.154.237; 4.I.154.238; 4.I.154.239; 4.I.154.154; 4.I.154.157;4.I.154.166; 4.I.154.169; 4.I.154.172; 4.I.154.175; 4.I.154.240;4.I.154.244; 4.I.157.228; 4.I.157.229; 4.I.157.230; 4.I.157.231;4.I.157.236; 4.I.157.237; 4.I.157.238; 4.I.157.239; 4.I.157.154;4.I.157.157; 4.I.157.166; 4.I.157.169; 4.I.157.172; 4.I.157.175;4.I.157.240; 4.I.157.244; 4.I.166.228; 4.I.166.229; 4.I.166.230;4.I.166.231; 4.I.166.236; 4.I.166.237; 4.I.166.238; 4.I.166.239;4.I.166.154; 4.I.166.157; 4.I.166.166; 4.I.166.169; 4.I.166.172;4.I.166.175; 4.I.166.240; 4.I.166.244; 4.I.169.228; 4.I.169.229;4.I.169.230; 4.I.169.231; 4.I.169.236; 4.I.169.237; 4.I.169.238;4.I.169.239; 4.I.169.154; 4.I.169.157; 4.I.169.166; 4.I.169.169;4.I.169.172; 4.I.169.175; 4.I.169.240; 4.I.169.244; 4.I.172.228;4.I.172.229; 4.I.172.230; 4.I.172.231; 4.I.172.236; 4.I.172.237;4.I.172.238; 4.I.172.239; 4.I.172.154; 4.I.172.157; 4.I.172.166;4.I.172.169; 4.I.172.172; 4.I.172.175; 4.I.172.240; 4.I.172.244;4.I.175.228; 4.I.175.229; 4.I.175.230; 4.I.175.231; 4.I.175.236;4.I.175.237; 4.I.175.238; 4.I.175.239; 4.I.175.154; 4.I.175.157;4.I.175.166; 4.I.175.169; 4.I.175.172; 4.I.175.175; 4.I.175.240;4.I.175.244; 4.I.240.228; 4.I.240.229; 4.I.240.230; 4.I.240.231;4.I.240.236; 4.I.240.237; 4.I.240.238; 4.I.240.239; 4.I.240.154;4.I.240.157; 4.I.240.166; 4.I.240.169; 4.I.240.172; 4.I.240.175;4.I.240.240; 4.I.240.244; 4.I.244.228; 4.I.244.229; 4.I.244.230;4.I.244.231; 4.I.244.236; 4.I.244.237; 4.I.244.238; 4.I.244.239;4.I.244.154; 4.I.244.157; 4.I.244.166; 4.I.244.169; 4.I.244.172;4.I.244.175; 4.I.244.240; 4.I.244.244; Prodrugs of 4.J 4.J.228.228;4.J.228.229; 4.J.228.230; 4.J.228.231; 4.J.228.236; 4.J.228.237;4.J.228.238; 4.J.228.239; 4.J.228.154; 4.J.228.157; 4.J.228.166;4.J.228.169; 4.J.228.172; 4.J.228.175; 4.J.228.240; 4.J.228.244;4.J.229.228; 4.J.229.229; 4.J.229.230; 4.J.229.231; 4.J.229.236;4.J.229.237; 4.J.229.238; 4.J.229.239; 4.J.229.154; 4.J.229.157;4.J.229.166; 4.J.229.169; 4.J.229.172; 4.J.229.175; 4.J.229.240;4.J.229.244; 4.J.230.228; 4.J.230.229; 4.J.230.230; 4.J.230.231;4.J.230.236; 4.J.230.237; 4.J.230.238; 4.J.230.239; 4.J.230.154;4.J.230.157; 4.J.230.166; 4.J.230.169; 4.J.230.172; 4.J.230.175;4.J.230.240; 4.J.230.244; 4.J.231.228; 4.J.231.229; 4.J.231.230;4.J.231.231; 4.J.231.236; 4.J.231.237; 4.J.231.238; 4.J.231.239;4.J.231.154; 4.J.231.157; 4.J.231.166; 4.J.231.169; 4.J.231.172;4.J.231.175; 4.J.231.240; 4.J.231.244; 4.J.236.228; 4.J.236.229;4.J.236.230; 4.J.236.231; 4.J.236.236; 4.J.236.237; 4.J.236.238;4.J.236.239; 4.J.236.154; 4.J.236.157; 4.J.236.166; 4.J.236.169;4.J.236.172; 4.J.236.175; 4.J.236.240; 4.J.236.244; 4.J.237.228;4.J.237.229; 4.J.237.230; 4.J.237.231; 4.J.237.236; 4.J.237.237;4.J.237.238; 4.J.237.239; 4.J.237.154; 4.J.237.157; 4.J.237.166;4.J.237.169; 4.J.237.172; 4.J.237.175; 4.J.237.240; 4.J.237.244;4.J.238.228; 4.J.238.229; 4.J.238.230; 4.J.238.231; 4.J.238.236;4.J.238.237; 4.J.238.238; 4.J.238.239; 4.J.238.154; 4.J.238.157;4.J.238.166; 4.J.238.169; 4.J.238.172; 4.J.238.175; 4.J.238.240;4.J.238.244; 4.J.239.228; 4.J.239.229; 4.J.239.230; 4.J.239.231;4.J.239.236; 4.J.239.237; 4.J.239.238; 4.J.239.239; 4.J.239.154;4.J.239.157; 4.J.239.166; 4.J.239.169; 4.J.239.172; 4.J.239.175;4.J.239.240; 4.J.239.244; 4.J.154.228; 4.J.154.229; 4.J.154.230;4.J.154.231; 4.J.154.236; 4.J.154.237; 4.J.154.238; 4.J.154.239;4.J.154.154; 4.J.154.157; 4.J.154.166; 4.J.154.169; 4.J.154.172;4.J.154.175; 4.J.154.240; 4.J.154.244; 4.J.157.228; 4.J.157.229;4.J.157.230; 4.J.157.231; 4.J.157.236; 4.J.157.237; 4.J.157.238;4.J.157.239; 4.J.157.154; 4.J.157.157; 4.J.157.166; 4.J.157.169;4.J.157.172; 4.J.157.175; 4.J.157.240; 4.J.157.244; 4.J.166.228;4.J.166.229; 4.J.166.230; 4.J.166.231; 4.J.166.236; 4.J.166.237;4.J.166.238; 4.J.166.239; 4.J.166.154; 4.J.166.157; 4.J.166.166;4.J.166.169; 4.J.166.172; 4.J.166.175; 4.J.166.240; 4.J.166.244;4.J.169.228; 4.J.169.229; 4.J.169.230; 4.J.169.231; 4.J.169.236;4.J.169.237; 4.J.169.238; 4.J.169.239; 4.J.169.154; 4.J.169.157;4.J.169.166; 4.J.169.169; 4.J.169.172; 4.J.169.175; 4.J.169.240;4.J.169.244; 4.J.172.228; 4.J.172.229; 4.J.172.230; 4.J.172.231;4.J.172.236; 4.J.172.237; 4.J.172.238; 4.J.172.239; 4.J.172.154;4.J.172.157; 4.J.172.166; 4.J.172.169; 4.J.172.172; 4.J.172.175;4.J.172.240; 4.J.172.244; 4.J.175.228; 4.J.175.229; 4.J.175.230;4.J.175.231; 4.J.175.236; 4.J.175.237; 4.J.175.238; 4.J.175.239;4.J.175.154; 4.J.175.157; 4.J.175.166; 4.J.175.169; 4.J.175.172;4.J.175.175; 4.J.175.240; 4.J.175.244; 4.J.240.228; 4.J.240.229;4.J.240.230; 4.J.240.231; 4.J.240.236; 4.J.240.237; 4.J.240.238;4.J.240.239; 4.J.240.154; 4.J.240.157; 4.J.240.166; 4.J.240.169;4.J.240.172; 4.J.240.175; 4.J.240.240; 4.J.240.244; 4.J.244.228;4.J.244.229; 4.J.244.230; 4.J.244.231; 4.J.244.236; 4.J.244.237;4.J.244.238; 4.J.244.239; 4.J.244.154; 4.J.244.157; 4.J.244.166;4.J.244.169; 4.J.244.172; 4.J.244.175; 4.J.244.240; 4.J.244.244;Prodrugs of 4.L 4.L.228.228; 4.L.228.229; 4.L.228.230; 4.L.228.231;4.L.228.236; 4.L.228.237; 4.L.228.238; 4.L.228.239; 4.L.228.154;4.L.228.157; 4.L.228.166; 4.L.228.169; 4.L.228.172; 4.L.228.175;4.L.228.240; 4.L.228.244; 4.L.229.228; 4.L.229.229; 4.L.229.230;4.L.229.231; 4.L.229.236; 4.L.229.237; 4.L.229.238; 4.L.229.239;4.L.229.154; 4.L.229.157; 4.L.229.166; 4.L.229.169; 4.L.229.172;4.L.229.175; 4.L.229.240; 4.L.229.244; 4.L.230.228; 4.L.230.229;4.L.230.230; 4.L.230.231; 4.L.230.236; 4.L.230.237; 4.L.230.238;4.L.230.239; 4.L.230.154; 4.L.230.157; 4.L.230.166; 4.L.230.169;4.L.230.172; 4.L.230.175; 4.L.230.240; 4.L.230.244; 4.L.231.228;4.L.231.229; 4.L.231.230; 4.L.231.231; 4.L.231.236; 4.L.231.237;4.L.231.238; 4.L.231.239; 4.L.231.154; 4.L.231.157; 4.L.231.166;4.L.231.169; 4.L.231.172; 4.L.231.175; 4.L.231.240; 4.L.231.244;4.L.236.228; 4.L.236.229; 4.L.236.230; 4.L.236.231; 4.L.236.236;4.L.236.237; 4.L.236.238; 4.L.236.239; 4.L.236.154; 4.L.236.157;4.L.236.166; 4.L.236.169; 4.L.236.172; 4.L.236.175; 4.L.236.240;4.L.236.244; 4.L.237.228; 4.L.237.229; 4.L.237.230; 4.L.237.231;4.L.237.236; 4.L.237.237; 4.L.237.238; 4.L.237.239; 4.L.237.154;4.L.237.157; 4.L.237.166; 4.L.237.169; 4.L.237.172; 4.L.237.175;4.L.237.240; 4.L.237.244; 4.L.238.228; 4.L.238.229; 4.L.238.230;4.L.238.231; 4.L.238.236; 4.L.238.237; 4.L.238.238; 4.L.238.239;4.L.238.154; 4.L.238.157; 4.L.238.166; 4.L.238.169; 4.L.238.172;4.L.238.175; 4.L.238.240; 4.L.238.244; 4.L.239.228; 4.L.239.229;4.L.239.230; 4.L.239.231; 4.L.239.236; 4.L.239.237; 4.L.239.238;4.L.239.239; 4.L.239.154; 4.L.239.157; 4.L.239.166; 4.L.239.169;4.L.239.172; 4.L.239.175; 4.L.239.240; 4.L.239.244; 4.L.154.228;4.L.154.229; 4.L.154.230; 4.L.154.231; 4.L.154.236; 4.L.154.237;4.L.154.238; 4.L.154.239; 4.L.154.154; 4.L.154.157; 4.L.154.166;4.L.154.169; 4.L.154.172; 4.L.154.175; 4.L.154.240; 4.L.154.244;4.L.157.228; 4.L.157.229; 4.L.157.230; 4.L.157.231; 4.L.157.236;4.L.157.237; 4.L.157.238; 4.L.157.239; 4.L.157.154; 4.L.157.157;4.L.157.166; 4.L.157.169; 4.L.157.172; 4.L.157.175; 4.L.157.240;4.L.157.244; 4.L.166.228; 4.L.166.229; 4.L.166.230; 4.L.166.231;4.L.166.236; 4.L.166.237; 4.L.166.238; 4.L.166.239; 4.L.166.154;4.L.166.157; 4.L.166.166; 4.L.166.169; 4.L.166.172; 4.L.166.175;4.L.166.240; 4.L.166.244; 4.L.169.228; 4.L.169.229; 4.L.169.230;4.L.169.231; 4.L.169.236; 4.L.169.237; 4.L.169.238; 4.L.169.239;4.L.169.154; 4.L.169.157; 4.L.169.166; 4.L.169.169; 4.L.169.172;4.L.169.175; 4.L.169.240; 4.L.169.244; 4.L.172.228; 4.L.172.229;4.L.172.230; 4.L.172.231; 4.L.172.236; 4.L.172.237; 4.L.172.238;4.L.172.239; 4.L.172.154; 4.L.172.157; 4.L.172.166; 4.L.172.169;4.L.172.172; 4.L.172.175; 4.L.172.240; 4.L.172.244; 4.L.175.228;4.L.175.229; 4.L.175.230; 4.L.175.231; 4.L.175.236; 4.L.175.237;4.L.175.238; 4.L.175.239; 4.L.175.154; 4.L.175.157; 4.L.175.166;4.L.175.169; 4.L.175.172; 4.L.175.175; 4.L.175.240; 4.L.175.244;4.L.240.228; 4.L.240.229; 4.L.240.230; 4.L.240.231; 4.L.240.236;4.L.240.237; 4.L.240.238; 4.L.240.239; 4.L.240.154; 4.L.240.157;4.L.240.166; 4.L.240.169; 4.L.240.172; 4.L.240.175; 4.L.240.240;4.L.240.244; 4.L.244.228; 4.L.244.229; 4.L.244.230; 4.L.244.231;4.L.244.236; 4.L.244.237; 4.L.244.238; 4.L.244.239; 4.L.244.154;4.L.244.157; 4.L.244.166; 4.L.244.169; 4.L.244.172; 4.L.244.175;4.L.244.240; 4.L.244.244; Prodrugs of 4.O 4.O.228.228; 4.O.228.229;4.O.228.230; 4.O.228.231; 4.O.228.236; 4.O.228.237; 4.O.228.238;4.O.228.239; 4.O.228.154; 4.O.228.157; 4.O.228.166; 4.O.228.169;4.O.228.172; 4.O.228.175; 4.O.228.240; 4.O.228.244; 4.O.229.228;4.O.229.229; 4.O.229.230; 4.O.229.231; 4.O.229.236; 4.O.229.237;4.O.229.238; 4.O.229.239; 4.O.229.154; 4.O.229.157; 4.O.229.166;4.O.229.169; 4.O.229.172; 4.O.229.175; 4.O.229.240; 4.O.229.244;4.O.230.228; 4.O.230.229; 4.O.230.230; 4.O.230.231; 4.O.230.236;4.O.230.237; 4.O.230.238; 4.O.230.239; 4.O.230.154; 4.O.230.157;4.O.230.166; 4.O.230.169; 4.O.230.172; 4.O.230.175; 4.O.230.240;4.O.230.244; 4.O.231.228; 4.O.231.229; 4.O.231.230; 4.O.231.231;4.O.231.236; 4.O.231.237; 4.O.231.238; 4.O.231.239; 4.O.231.154;4.O.231.157; 4.O.231.166; 4.O.231.169; 4.O.231.172; 4.O.231.175;4.O.231.240; 4.O.231.244; 4.O.236.228; 4.O.236.229; 4.O.236.230;4.O.236.231; 4.O.236.236; 4.O.236.237; 4.O.236.238; 4.O.236.239;4.O.236.154; 4.O.236.157; 4.O.236.166; 4.O.236.169; 4.O.236.172;4.O.236.175; 4.O.236.240; 4.O.236.244; 4.O.237.228; 4.O.237.229;4.O.237.230; 4.O.237.231; 4.O.237.236; 4.O.237.237; 4.O.237.238;4.O.237.239; 4.O.237.154; 4.O.237.157; 4.O.237.166; 4.O.237.169;4.O.237.172; 4.O.237.175; 4.O.237.240; 4.O.237.244; 4.O.238.228;4.O.238.229; 4.O.238.230; 4.O.238.231; 4.O.238.236; 4.O.238.237;4.O.238.238; 4.O.238.239; 4.O.238.154; 4.O.238.157; 4.O.238.166;4.O.238.169; 4.O.238.172; 4.O.238.175; 4.O.238.240; 4.O.238.244;4.O.239.228; 4.O.239.229; 4.O.239.230; 4.O.239.231; 4.O.239.236;4.O.239.237; 4.O.239.238; 4.O.239.239; 4.O.239.154; 4.O.239.157;4.O.239.166; 4.O.239.169; 4.O.239.172; 4.O.239.175; 4.O.239.240;4.O.239.244; 4.O.154.228; 4.O.154.229; 4.O.154.230; 4.O.154.231;4.O.154.236; 4.O.154.237; 4.O.154.238; 4.O.154.239; 4.O.154.154;4.O.154.157; 4.O.154.166; 4.O.154.169; 4.O.154.172; 4.O.154.175;4.O.154.240; 4.O.154.244; 4.O.157.228; 4.O.157.229; 4.O.157.230;4.O.157.231; 4.O.157.236; 4.O.157.237; 4.O.157.238; 4.O.157.239;4.O.157.154; 4.O.157.157; 4.O.157.166; 4.O.157.169; 4.O.157.172;4.O.157.175; 4.O.157.240; 4.O.157.244; 4.O.166.228; 4.O.166.229;4.O.166.230; 4.O.166.231; 4.O.166.236; 4.O.166.237; 4.O.166.238;4.O.166.239; 4.O.166.154; 4.O.166.157; 4.O.166.166; 4.O.166.169;4.O.166.172; 4.O.166.175; 4.O.166.240; 4.O.166.244; 4.O.169.228;4.O.169.229; 4.O.169.230; 4.O.169.231; 4.O.169.236; 4.O.169.237;4.O.169.238; 4.O.169.239; 4.O.169.154; 4.O.169.157; 4.O.169.166;4.O.169.169; 4.O.169.172; 4.O.169.175; 4.O.169.240; 4.O.169.244;4.O.172.228; 4.O.172.229; 4.O.172.230; 4.O.172.231; 4.O.172.236;4.O.172.237; 4.O.172.238; 4.O.172.239; 4.O.172.154; 4.O.172.157;4.O.172.166; 4.O.172.169; 4.O.172.172; 4.O.172.175; 4.O.172.240;4.O.172.244; 4.O.175.228; 4.O.175.229; 4.O.175.230; 4.O.175.231;4.O.175.236; 4.O.175.237; 4.O.175.238; 4.O.175.239; 4.O.175.154;4.O.175.157; 4.O.175.166; 4.O.175.169; 4.O.175.172; 4.O.175.175;4.O.175.240; 4.O.175.244; 4.O.240.228; 4.O.240.229; 4.O.240.230;4.O.240.231; 4.O.240.236; 4.O.240.237; 4.O.240.238; 4.O.240.239;4.O.240.154; 4.O.240.157; 4.O.240.166; 4.O.240.169; 4.O.240.172;4.O.240.175; 4.O.240.240; 4.O.240.244; 4.O.244.228; 4.O.244.229;4.O.244.230; 4.O.244.231; 4.O.244.236; 4.O.244.237; 4.O.244.238;4.O.244.239; 4.O.244.154; 4.O.244.157; 4.O.244.166; 4.O.244.169;4.O.244.172; 4.O.244.175; 4.O.244.240; 4.O.244.244; Prodrugs of 4.P4.P.228.228; 4.P.228.229; 4.P.228.230; 4.P.228.231; 4.P.228.236;4.P.228.237; 4.P.228.238; 4.P.228.239; 4.P.228.154; 4.P.228.157;4.P.228.166; 4.P.228.169; 4.P.228.172; 4.P.228.175; 4.P.228.240;4.P.228.244; 4.P.229.228; 4.P.229.229; 4.P.229.230; 4.P.229.231;4.P.229.236; 4.P.229.237; 4.P.229.238; 4.P.229.239; 4.P.229.154;4.P.229.157; 4.P.229.166; 4.P.229.169; 4.P.229.172; 4.P.229.175;4.P.229.240; 4.P.229.244; 4.P.230.228; 4.P.230.229; 4.P.230.230;4.P.230.231; 4.P.230.236; 4.P.230.237; 4.P.230.238; 4.P.230.239;4.P.230.154; 4.P.230.157; 4.P.230.166; 4.P.230.169; 4.P.230.172;4.P.230.175; 4.P.230.240; 4.P.230.244; 4.P.231.228; 4.P.231.229;4.P.231.230; 4.P.231.231; 4.P.231.236; 4.P.231.237; 4.P.231.238;4.P.231.239; 4.P.231.154; 4.P.231.157; 4.P.231.166; 4.P.231.169;4.P.231.172; 4.P.231.175; 4.P.231.240; 4.P.231.244; 4.P.236.228;4.P.236.229; 4.P.236.230; 4.P.236.231; 4.P.236.236; 4.P.236.237;4.P.236.238; 4.P.236.239; 4.P.236.154; 4.P.236.157; 4.P.236.166;4.P.236.169; 4.P.236.172; 4.P.236.175; 4.P.236.240; 4.P.236.244;4.P.237.228; 4.P.237.229; 4.P.237.230; 4.P.237.231; 4.P.237.236;4.P.237.237; 4.P.237.238; 4.P.237.239; 4.P.237.154; 4.P.237.157;4.P.237.166; 4.P.237.169; 4.P.237.172; 4.P.237.175; 4.P.237.240;4.P.237.244; 4.P.238.228; 4.P.238.229; 4.P.238.230; 4.P.238.231;4.P.238.236; 4.P.238.237; 4.P.238.238; 4.P.238.239; 4.P.238.154;4.P.238.157; 4.P.238.166; 4.P.238.169; 4.P.238.172; 4.P.238.175;4.P.238.240; 4.P.238.244; 4.P.239.228; 4.P.239.229; 4.P.239.230;4.P.239.231; 4.P.239.236; 4.P.239.237; 4.P.239.238; 4.P.239.239;4.P.239.154; 4.P.239.157; 4.P.239.166; 4.P.239.169; 4.P.239.172;4.P.239.175; 4.P.239.240; 4.P.239.244; 4.P.154.228; 4.P.154.229;4.P.154.230; 4.P.154.231; 4.P.154.236; 4.P.154.237; 4.P.154.238;4.P.154.239; 4.P.154.154; 4.P.154.157; 4.P.154.166; 4.P.154.169;4.P.154.172; 4.P.154.175; 4.P.154.240; 4.P.154.244; 4.P.157.228;4.P.157.229; 4.P.157.230; 4.P.157.231; 4.P.157.236; 4.P.157.237;4.P.157.238; 4.P.157.239; 4.P.157.154; 4.P.157.157; 4.P.157.166;4.P.157.169; 4.P.157.172; 4.P.157.175; 4.P.157.240; 4.P.157.244;4.P.166.228; 4.P.166.229; 4.P.166.230; 4.P.166.231; 4.P.166.236;4.P.166.237; 4.P.166.238; 4.P.166.239; 4.P.166.154; 4.P.166.157;4.P.166.166; 4.P.166.169; 4.P.166.172; 4.P.166.175; 4.P.166.240;4.P.166.244; 4.P.169.228; 4.P.169.229; 4.P.169.230; 4.P.169.231;4.P.169.236; 4.P.169.237; 4.P.169.238; 4.P.169.239; 4.P.169.154;4.P.169.157; 4.P.169.166; 4.P.169.169; 4.P.169.172; 4.P.169.175;4.P.169.240; 4.P.169.244; 4.P.172.228; 4.P.172.229; 4.P.172.230;4.P.172.231; 4.P.172.236; 4.P.172.237; 4.P.172.238; 4.P.172.239;4.P.172.154; 4.P.172.157; 4.P.172.166; 4.P.172.169; 4.P.172.172;4.P.172.175; 4.P.172.240; 4.P.172.244; 4.P.175.228; 4.P.175.229;4.P.175.230; 4.P.175.231; 4.P.175.236; 4.P.175.237; 4.P.175.238;4.P.175.239; 4.P.175.154; 4.P.175.157; 4.P.175.166; 4.P.175.169;4.P.175.172; 4.P.175.175; 4.P.175.240; 4.P.175.244; 4.P.240.228;4.P.240.229; 4.P.240.230; 4.P.240.231; 4.P.240.236; 4.P.240.237;4.P.240.238; 4.P.240.239; 4.P.240.154; 4.P.240.157; 4.P.240.166;4.P.240.169; 4.P.240.172; 4.P.240.175; 4.P.240.240; 4.P.240.244;4.P.244.228; 4.P.244.229; 4.P.244.230; 4.P.244.231; 4.P.244.236;4.P.244.237; 4.P.244.238; 4.P.244.239; 4.P.244.154; 4.P.244.157;4.P.244.166; 4.P.244.169; 4.P.244.172; 4.P.244.175; 4.P.244.240;4.P.244.244; Prodrugs of 4.U 4.U.228.228; 4.U.228.229; 4.U.228.230;4.U.228.231; 4.U.228.236; 4.U.228.237; 4.U.228.238; 4.U.228.239;4.U.228.154; 4.U.228.157; 4.U.228.166; 4.U.228.169; 4.U.228.172;4.U.228.175; 4.U.228.240; 4.U.228.244; 4.U.229.228; 4.U.229.229;4.U.229.230; 4.U.229.231; 4.U.229.236; 4.U.229.237; 4.U.229.238;4.U.229.239; 4.U.229.154; 4.U.229.157; 4.U.229.166; 4.U.229.169;4.U.229.172; 4.U.229.175; 4.U.229.240; 4.U.229.244; 4.U.230.228;4.U.230.229; 4.U.230.230; 4.U.230.231; 4.U.230.236; 4.U.230.237;4.U.230.238; 4.U.230.239; 4.U.230.154; 4.U.230.157; 4.U.230.166;4.U.230.169; 4.U.230.172; 4.U.230.175; 4.U.230.240; 4.U.230.244;4.U.231.228; 4.U.231.229; 4.U.231.230; 4.U.231.231; 4.U.231.236;4.U.231.237; 4.U.231.238; 4.U.231.239; 4.U.231.154; 4.U.231.157;4.U.231.166; 4.U.231.169; 4.U.231.172; 4.U.231.175; 4.U.231.240;4.U.231.244; 4.U.236.228; 4.U.236.229; 4.U.236.230; 4.U.236.231;4.U.236.236; 4.U.236.237; 4.U.236.238; 4.U.236.239; 4.U.236.154;4.U.236.157; 4.U.236.166; 4.U.236.169; 4.U.236.172; 4.U.236.175;4.U.236.240; 4.U.236.244; 4.U.237.228; 4.U.237.229; 4.U.237.230;4.U.237.231; 4.U.237.236; 4.U.237.237; 4.U.237.238; 4.U.237.239;4.U.237.154; 4.U.237.157; 4.U.237.166; 4.U.237.169; 4.U.237.172;4.U.237.175; 4.U.237.240; 4.U.237.244; 4.U.238.228; 4.U.238.229;4.U.238.230; 4.U.238.231; 4.U.238.236; 4.U.238.237; 4.U.238.238;4.U.238.239; 4.U.238.154; 4.U.238.157; 4.U.238.166; 4.U.238.169;4.U.238.172; 4.U.238.175; 4.U.238.240; 4.U.238.244; 4.U.239.228;4.U.239.229; 4.U.239.230; 4.U.239.231; 4.U.239.236; 4.U.239.237;4.U.239.238; 4.U.239.239; 4.U.239.154; 4.U.239.157; 4.U.239.166;4.U.239.169; 4.U.239.172; 4.U.239.175; 4.U.239.240; 4.U.239.244;4.U.154.228; 4.U.154.229; 4.U.154.230; 4.U.154.231; 4.U.154.236;4.U.154.237; 4.U.154.238; 4.U.154.239; 4.U.154.154; 4.U.154.157;4.U.154.166; 4.U.154.169; 4.U.154.172; 4.U.154.175; 4.U.154.240;4.U.154.244; 4.U.157.228; 4.U.157.229; 4.U.157.230; 4.U.157.231;4.U.157.236; 4.U.157.237; 4.U.157.238; 4.U.157.239; 4.U.157.154;4.U.157.157; 4.U.157.166; 4.U.157.169; 4.U.157.172; 4.U.157.175;4.U.157.240; 4.U.157.244; 4.U.166.228; 4.U.166.229; 4.U.166.230;4.U.166.231; 4.U.166.236; 4.U.166.237; 4.U.166.238; 4.U.166.239;4.U.166.154; 4.U.166.157; 4.U.166.166; 4.U.166.169; 4.U.166.172;4.U.166.175; 4.U.166.240; 4.U.166.244; 4.U.169.228; 4.U.169.229;4.U.169.230; 4.U.169.231; 4.U.169.236; 4.U.169.237; 4.U.169.238;4.U.169.239; 4.U.169.154; 4.U.169.157; 4.U.169.166; 4.U.169.169;4.U.169.172; 4.U.169.175; 4.U.169.240; 4.U.169.244; 4.U.172.228;4.U.172.229; 4.U.172.230; 4.U.172.231; 4.U.172.236; 4.U.172.237;4.U.172.238; 4.U.172.239; 4.U.172.154; 4.U.172.157; 4.U.172.166;4.U.172.169; 4.U.172.172; 4.U.172.175; 4.U.172.240; 4.U.172.244;4.U.175.228; 4.U.175.229; 4.U.175.230; 4.U.175.231; 4.U.175.236;4.U.175.237; 4.U.175.238; 4.U.175.239; 4.U.175.154; 4.U.175.157;4.U.175.166; 4.U.175.169; 4.U.175.172; 4.U.175.175; 4.U.175.240;4.U.175.244; 4.U.240.228; 4.U.240.229; 4.U.240.230; 4.U.240.231;4.U.240.236; 4.U.240.237; 4.U.240.238; 4.U.240.239; 4.U.240.154;4.U.240.157; 4.U.240.166; 4.U.240.169; 4.U.240.172; 4.U.240.175;4.U.240.240; 4.U.240.244; 4.U.244.228; 4.U.244.229; 4.U.244.230;4.U.244.231; 4.U.244.236; 4.U.244.237; 4.U.244.238; 4.U.244.239;4.U.244.154; 4.U.244.157; 4.U.244.166; 4.U.244.169; 4.U.244.172;4.U.244.175; 4.U.244.240; 4.U.244.244; Prodrugs of 4.W 4.W.228.228;4.W.228.229; 4.W.228.230; 4.W.228.231; 4.W.228.236; 4.W.228.237;4.W.228.238; 4.W.228.239; 4.W.228.154; 4.W.228.157; 4.W.228.166;4.W.228.169; 4.W.228.172; 4.W.228.175; 4.W.228.240; 4.W.228.244;4.W.229.228; 4.W.229.229; 4.W.229.230; 4.W.229.231; 4.W.229.236;4.W.229.237; 4.W.229.238; 4.W.229.239; 4.W.229.154; 4.W.229.157;4.W.229.166; 4.W.229.169; 4.W.229.172; 4.W.229.175; 4.W.229.240;4.W.229.244; 4.W.230.228; 4.W.230.229; 4.W.230.230; 4.W.230.231;4.W.230.236; 4.W.230.237; 4.W.230.238; 4.W.230.239; 4.W.230.154;4.W.230.157; 4.W.230.166; 4.W.230.169; 4.W.230.172; 4.W.230.175;4.W.230.240; 4.W.230.244; 4.W.231.228; 4.W.231.229; 4.W.231.230;4.W.231.231; 4.W.231.236; 4.W.231.237; 4.W.231.238; 4.W.231.239;4.W.231.154; 4.W.231.157; 4.W.231.166; 4.W.231.169; 4.W.231.172;4.W.231.175; 4.W.231.240; 4.W.231.244; 4.W.236.228; 4.W.236.229;4.W.236.230; 4.W.236.231; 4.W.236.236; 4.W.236.237; 4.W.236.238;4.W.236.239; 4.W.236.154; 4.W.236.157; 4.W.236.166; 4.W.236.169;4.W.236.172; 4.W.236.175; 4.W.236.240; 4.W.236.244; 4.W.237.228;4.W.237.229; 4.W.237.230; 4.W.237.231; 4.W.237.236; 4.W.237.237;4.W.237.238; 4.W.237.239; 4.W.237.154; 4.W.237.157; 4.W.237.166;4.W.237.169; 4.W.237.172; 4.W.237.175; 4.W.237.240; 4.W.237.244;4.W.238.228; 4.W.238.229; 4.W.238.230; 4.W.238.231; 4.W.238.236;4.W.238.237; 4.W.238.238; 4.W.238.239; 4.W.238.154; 4.W.238.157;4.W.238.166; 4.W.238.169; 4.W.238.172; 4.W.238.175; 4.W.238.240;4.W.238.244; 4.W.239.228; 4.W.239.229; 4.W.239.230; 4.W.239.231;4.W.239.236; 4.W.239.237; 4.W.239.238; 4.W.239.239; 4.W.239.154;4.W.239.157; 4.W.239.166; 4.W.239.169; 4.W.239.172; 4.W.239.175;4.W.239.240; 4.W.239.244; 4.W.154.228; 4.W.154.229; 4.W.154.230;4.W.154.231; 4.W.154.236; 4.W.154.237; 4.W.154.238; 4.W.154.239;4.W.154.154; 4.W.154.157; 4.W.154.166; 4.W.154.169; 4.W.154.172;4.W.154.175; 4.W.154.240; 4.W.154.244; 4.W.157.228; 4.W.157.229;4.W.157.230; 4.W.157.231; 4.W.157.236; 4.W.157.237; 4.W.157.238;4.W.157.239; 4.W.157.154; 4.W.157.157; 4.W.157.166; 4.W.157.169;4.W.157.172; 4.W.157.175; 4.W.157.240; 4.W.157.244; 4.W.166.228;4.W.166.229; 4.W.166.230; 4.W.166.231; 4.W.166.236; 4.W.166.237;4.W.166.238; 4.W.166.239; 4.W.166.154; 4.W.166.157; 4.W.166.166;4.W.166.169; 4.W.166.172; 4.W.166.175; 4.W.166.240; 4.W.166.244;4.W.169.228; 4.W.169.229; 4.W.169.230; 4.W.169.231; 4.W.169.236;4.W.169.237; 4.W.169.238; 4.W.169.239; 4.W.169.154; 4.W.169.157;4.W.169.166; 4.W.169.169; 4.W.169.172; 4.W.169.175; 4.W.169.240;4.W.169.244; 4.W.172.228; 4.W.172.229; 4.W.172.230; 4.W.172.231;4.W.172.236; 4.W.172.237; 4.W.172.238; 4.W.172.239; 4.W.172.154;4.W.172.157; 4.W.172.166; 4.W.172.169; 4.W.172.172; 4.W.172.175;4.W.172.240; 4.W.172.244; 4.W.175.228; 4.W.175.229; 4.W.175.230;4.W.175.231; 4.W.175.236; 4.W.175.237; 4.W.175.238; 4.W.175.239;4.W.175.154; 4.W.175.157; 4.W.175.166; 4.W.175.169; 4.W.175.172;4.W.175.175; 4.W.175.240; 4.W.175.244; 4.W.240.228; 4.W.240.229;4.W.240.230; 4.W.240.231; 4.W.240.236; 4.W.240.237; 4.W.240.238;4.W.240.239; 4.W.240.154; 4.W.240.157; 4.W.240.166; 4.W.240.169;4.W.240.172; 4.W.240.175; 4.W.240.240; 4.W.240.244; 4.W.244.228;4.W.244.229; 4.W.244.230; 4.W.244.231; 4.W.244.236; 4.W.244.237;4.W.244.238; 4.W.244.239; 4.W.244.154; 4.W.244.157; 4.W.244.166;4.W.244.169; 4.W.244.172; 4.W.244.175; 4.W.244.240; 4.W.244.244;Prodrugs of 4.Y 4.Y.228.228; 4.Y.228.229; 4.Y.228.230; 4.Y.228.231;4.Y.228.236; 4.Y.228.237; 4.Y.228.238; 4.Y.228.239; 4.Y.228.154;4.Y.228.157; 4.Y.228.166; 4.Y.228.169; 4.Y.228.172; 4.Y.228.175;4.Y.228.240; 4.Y.228.244; 4.Y.229.228; 4.Y.229.229; 4.Y.229.230;4.Y.229.231; 4.Y.229.236; 4.Y.229.237; 4.Y.229.238; 4.Y.229.239;4.Y.229.154; 4.Y.229.157; 4.Y.229.166; 4.Y.229.169; 4.Y.229.172;4.Y.229.175; 4.Y.229.240; 4.Y.229.244; 4.Y.230.228; 4.Y.230.229;4.Y.230.230; 4.Y.230.231; 4.Y.230.236; 4.Y.230.237; 4.Y.230.238;4.Y.230.239; 4.Y.230.154; 4.Y.230.157; 4.Y.230.166; 4.Y.230.169;4.Y.230.172; 4.Y.230.175; 4.Y.230.240; 4.Y.230.244; 4.Y.231.228;4.Y.231.229; 4.Y.231.230; 4.Y.231.231; 4.Y.231.236; 4.Y.231.237;4.Y.231.238; 4.Y.231.239; 4.Y.231.154; 4.Y.231.157; 4.Y.231.166;4.Y.231.169; 4.Y.231.172; 4.Y.231.175; 4.Y.231.240; 4.Y.231.244;4.Y.236.228; 4.Y.236.229; 4.Y.236.230; 4.Y.236.231; 4.Y.236.236;4.Y.236.237; 4.Y.236.238; 4.Y.236.239; 4.Y.236.154; 4.Y.236.157;4.Y.236.166; 4.Y.236.169; 4.Y.236.172; 4.Y.236.175; 4.Y.236.240;4.Y.236.244; 4.Y.237.228; 4.Y.237.229; 4.Y.237.230; 4.Y.237.231;4.Y.237.236; 4.Y.237.237; 4.Y.237.238; 4.Y.237.239; 4.Y.237.154;4.Y.237.157; 4.Y.237.166; 4.Y.237.169; 4.Y.237.172; 4.Y.237.175;4.Y.237.240; 4.Y.237.244; 4.Y.238.228; 4.Y.238.229; 4.Y.238.230;4.Y.238.231; 4.Y.238.236; 4.Y.238.237; 4.Y.238.238; 4.Y.238.239;4.Y.238.154; 4.Y.238.157; 4.Y.238.166; 4.Y.238.169; 4.Y.238.172;4.Y.238.175; 4.Y.238.240; 4.Y.238.244; 4.Y.239.228; 4.Y.239.229;4.Y.239.230; 4.Y.239.231; 4.Y.239.236; 4.Y.239.237; 4.Y.239.238;4.Y.239.239; 4.Y.239.154; 4.Y.239.157; 4.Y.239.166; 4.Y.239.169;4.Y.239.172; 4.Y.239.175; 4.Y.239.240; 4.Y.239.244; 4.Y.154.228;4.Y.154.229; 4.Y.154.230; 4.Y.154.231; 4.Y.154.236; 4.Y.154.237;4.Y.154.238; 4.Y.154.239; 4.Y.154.154; 4.Y.154.157; 4.Y.154.166;4.Y.154.169; 4.Y.154.172; 4.Y.154.175; 4.Y.154.240; 4.Y.154.244;4.Y.157.228; 4.Y.157.229; 4.Y.157.230; 4.Y.157.231; 4.Y.157.236;4.Y.157.237; 4.Y.157.238; 4.Y.157.239; 4.Y.157.154; 4.Y.157.157;4.Y.157.166; 4.Y.157.169; 4.Y.157.172; 4.Y.157.175; 4.Y.157.240;4.Y.157.244; 4.Y.166.228; 4.Y.166.229; 4.Y.166.230; 4.Y.166.231;4.Y.166.236; 4.Y.166.237; 4.Y.166.238; 4.Y.166.239; 4.Y.166.154;4.Y.166.157; 4.Y.166.166; 4.Y.166.169; 4.Y.166.172; 4.Y.166.175;4.Y.166.240; 4.Y.166.244; 4.Y.169.228; 4.Y.169.229; 4.Y.169.230;4.Y.169.231; 4.Y.169.236; 4.Y.169.237; 4.Y.169.238; 4.Y.169.239;4.Y.169.154; 4.Y.169.157; 4.Y.169.166; 4.Y.169.169; 4.Y.169.172;4.Y.169.175; 4.Y.169.240; 4.Y.169.244; 4.Y.172.228; 4.Y.172.229;4.Y.172.230; 4.Y.172.231; 4.Y.172.236; 4.Y.172.237; 4.Y.172.238;4.Y.172.239; 4.Y.172.154; 4.Y.172.157; 4.Y.172.166; 4.Y.172.169;4.Y.172.172; 4.Y.172.175; 4.Y.172.240; 4.Y.172.244; 4.Y.175.228;4.Y.175.229; 4.Y.175.230; 4.Y.175.231; 4.Y.175.236; 4.Y.175.237;4.Y.175.238; 4.Y.175.239; 4.Y.175.154; 4.Y.175.157; 4.Y.175.166;4.Y.175.169; 4.Y.175.172; 4.Y.175.175; 4.Y.175.240; 4.Y.175.244;4.Y.240.228; 4.Y.240.229; 4.Y.240.230; 4.Y.240.231; 4.Y.240.236;4.Y.240.237; 4.Y.240.238; 4.Y.240.239; 4.Y.240.154; 4.Y.240.157;4.Y.240.166; 4.Y.240.169; 4.Y.240.172; 4.Y.240.175; 4.Y.240.240;4.Y.240.244; 4.Y.244.228; 4.Y.244.229; 4.Y.244.230; 4.Y.244.231;4.Y.244.236; 4.Y.244.237; 4.Y.244.238; 4.Y.244.239; 4.Y.244.154;4.Y.244.157; 4.Y.244.166; 4.Y.244.169; 4.Y.244.172; 4.Y.244.175;4.Y.244.240; 4.Y.244.244; Prodrugs of 5.B 5.B.228.228; 5.B.228.229;5.B.228.230; 5.B.228.231; 5.B.228.236; 5.B.228.237; 5.B.228.238;5.B.228.239; 5.B.228.154; 5.B.228.157; 5.B.228.166; 5.B.228.169;5.B.228.172; 5.B.228.175; 5.B.228.240; 5.B.228.244; 5.B.229.228;5.B.229.229; 5.B.229.230; 5.B.229.231; 5.B.229.236; 5.B.229.237;5.B.229.238; 5.B.229.239; 5.B.229.154; 5.B.229.157; 5.B.229.166;5.B.229.169; 5.B.229.172; 5.B.229.175; 5.B.229.240; 5.B.229.244;5.B.230.228; 5.B.230.229; 5.B.230.230; 5.B.230.231; 5.B.230.236;5.B.230.237; 5.B.230.238; 5.B.230.239; 5.B.230.154; 5.B.230.157;5.B.230.166; 5.B.230.169; 5.B.230.172; 5.B.230.175; 5.B.230.240;5.B.230.244; 5.B.231.228; 5.B.231.229; 5.B.231.230; 5.B.231.231;5.B.231.236; 5.B.231.237; 5.B.231.238; 5.B.231.239; 5.B.231.154;5.B.231.157; 5.B.231.166; 5.B.231.169; 5.B.231.172; 5.B.231.175;5.B.231.240; 5.B.231.244; 5.B.236.228; 5.B.236.229; 5.B.236.230;5.B.236.231; 5.B.236.236; 5.B.236.237; 5.B.236.238; 5.B.236.239;5.B.236.154; 5.B.236.157; 5.B.236.166; 5.B.236.169; 5.B.236.172;5.B.236.175; 5.B.236.240; 5.B.236.244; 5.B.237.228; 5.B.237.229;5.B.237.230; 5.B.237.231; 5.B.237.236; 5.B.237.237; 5.B.237.238;5.B.237.239; 5.B.237.154; 5.B.237.157; 5.B.237.166; 5.B.237.169;5.B.237.172; 5.B.237.175; 5.B.237.240; 5.B.237.244; 5.B.238.228;5.B.238.229; 5.B.238.230; 5.B.238.231; 5.B.238.236; 5.B.238.237;5.B.238.238; 5.B.238.239; 5.B.238.154; 5.B.238.157; 5.B.238.166;5.B.238.169; 5.B.238.172; 5.B.238.175; 5.B.238.240; 5.B.238.244;5.B.239.228; 5.B.239.229; 5.B.239.230; 5.B.239.231; 5.B.239.236;5.B.239.237; 5.B.239.238; 5.B.239.239; 5.B.239.154; 5.B.239.157;5.B.239.166; 5.B.239.169; 5.B.239.172; 5.B.239.175; 5.B.239.240;5.B.239.244; 5.B.154.228; 5.B.154.229; 5.B.154.230; 5.B.154.231;5.B.154.236; 5.B.154.237; 5.B.154.238; 5.B.154.239; 5.B.154.154;5.B.154.157; 5.B.154.166; 5.B.154.169; 5.B.154.172; 5.B.154.175;5.B.154.240; 5.B.154.244; 5.B.157.228; 5.B.157.229; 5.B.157.230;5.B.157.231; 5.B.157.236; 5.B.157.237; 5.B.157.238; 5.B.157.239;5.B.157.154; 5.B.157.157; 5.B.157.166; 5.B.157.169; 5.B.157.172;5.B.157.175; 5.B.157.240; 5.B.157.244; 5.B.166.228; 5.B.166.229;5.B.166.230; 5.B.166.231; 5.B.166.236; 5.B.166.237; 5.B.166.238;5.B.166.239; 5.B.166.154; 5.B.166.157; 5.B.166.166; 5.B.166.169;5.B.166.172; 5.B.166.175; 5.B.166.240; 5.B.166.244; 5.B.169.228;5.B.169.229; 5.B.169.230; 5.B.169.231; 5.B.169.236; 5.B.169.237;5.B.169.238; 5.B.169.239; 5.B.169.154; 5.B.169.157; 5.B.169.166;5.B.169.169; 5.B.169.172; 5.B.169.175; 5.B.169.240; 5.B.169.244;5.B.172.228; 5.B.172.229; 5.B.172.230; 5.B.172.231; 5.B.172.236;5.B.172.237; 5.B.172.238; 5.B.172.239; 5.B.172.154; 5.B.172.157;5.B.172.166; 5.B.172.169; 5.B.172.172; 5.B.172.175; 5.B.172.240;5.B.172.244; 5.B.175.228; 5.B.175.229; 5.B.175.230; 5.B.175.231;5.B.175.236; 5.B.175.237; 5.B.175.238; 5.B.175.239; 5.B.175.154;5.B.175.157; 5.B.175.166; 5.B.175.169; 5.B.175.172; 5.B.175.175;5.B.175.240; 5.B.175.244; 5.B.240.228; 5.B.240.229; 5.B.240.230;5.B.240.231; 5.B.240.236; 5.B.240.237; 5.B.240.238; 5.B.240.239;5.B.240.154; 5.B.240.157; 5.B.240.166; 5.B.240.169; 5.B.240.172;5.B.240.175; 5.B.240.240; 5.B.240.244; 5.B.244.228; 5.B.244.229;5.B.244.230; 5.B.244.231; 5.B.244.236; 5.B.244.237; 5.B.244.238;5.B.244.239; 5.B.244.154; 5.B.244.157; 5.B.244.166; 5.B.244.169;5.B.244.172; 5.B.244.175; 5.B.244.240; 5.B.244.244; Prodrugs of 5.D5.D.228.228; 5.D.228.229; 5.D.228.230; 5.D.228.231; 5.D.228.236;5.D.228.237; 5.D.228.238; 5.D.228.239; 5.D.228.154; 5.D.228.157;5.D.228.166; 5.D.228.169; 5.D.228.172; 5.D.228.175; 5.D.228.240;5.D.228.244; 5.D.229.228; 5.D.229.229; 5.D.229.230; 5.D.229.231;5.D.229.236; 5.D.229.237; 5.D.229.238; 5.D.229.239; 5.D.229.154;5.D.229.157; 5.D.229.166; 5.D.229.169; 5.D.229.172; 5.D.229.175;5.D.229.240; 5.D.229.244; 5.D.230.228; 5.D.230.229; 5.D.230.230;5.D.230.231; 5.D.230.236; 5.D.230.237; 5.D.230.238; 5.D.230.239;5.D.230.154; 5.D.230.157; 5.D.230.166; 5.D.230.169; 5.D.230.172;5.D.230.175; 5.D.230.240; 5.D.230.244; 5.D.231.228; 5.D.231.229;5.D.231.230; 5.D.231.231; 5.D.231.236; 5.D.231.237; 5.D.231.238;5.D.231.239; 5.D.231.154; 5.D.231.157; 5.D.231.166; 5.D.231.169;5.D.231.172; 5.D.231.175; 5.D.231.240; 5.D.231.244; 5.D.236.228;5.D.236.229; 5.D.236.230; 5.D.236.231; 5.D.236.236; 5.D.236.237;5.D.236.238; 5.D.236.239; 5.D.236.154; 5.D.236.157; 5.D.236.166;5.D.236.169; 5.D.236.172; 5.D.236.175; 5.D.236.240; 5.D.236.244;5.D.237.228; 5.D.237.229; 5.D.237.230; 5.D.237.231; 5.D.237.236;5.D.237.237; 5.D.237.238; 5.D.237.239; 5.D.237.154; 5.D.237.157;5.D.237.166; 5.D.237.169; 5.D.237.172; 5.D.237.175; 5.D.237.240;5.D.237.244; 5.D.238.228; 5.D.238.229; 5.D.238.230; 5.D.238.231;5.D.238.236; 5.D.238.237; 5.D.238.238; 5.D.238.239; 5.D.238.154;5.D.238.157; 5.D.238.166; 5.D.238.169; 5.D.238.172; 5.D.238.175;5.D.238.240; 5.D.238.244; 5.D.239.228; 5.D.239.229; 5.D.239.230;5.D.239.231; 5.D.239.236; 5.D.239.237; 5.D.239.238; 5.D.239.239;5.D.239.154; 5.D.239.157; 5.D.239.166; 5.D.239.169; 5.D.239.172;5.D.239.175; 5.D.239.240; 5.D.239.244; 5.D.154.228; 5.D.154.229;5.D.154.230; 5.D.154.231; 5.D.154.236; 5.D.154.237; 5.D.154.238;5.D.154.239; 5.D.154.154; 5.D.154.157; 5.D.154.166; 5.D.154.169;5.D.154.172; 5.D.154.175; 5.D.154.240; 5.D.154.244; 5.D.157.228;5.D.157.229; 5.D.157.230; 5.D.157.231; 5.D.157.236; 5.D.157.237;5.D.157.238; 5.D.157.239; 5.D.157.154; 5.D.157.157; 5.D.157.166;5.D.157.169; 5.D.157.172; 5.D.157.175; 5.D.157.240; 5.D.157.244;5.D.166.228; 5.D.166.229; 5.D.166.230; 5.D.166.231; 5.D.166.236;5.D.166.237; 5.D.166.238; 5.D.166.239; 5.D.166.154; 5.D.166.157;5.D.166.166; 5.D.166.169; 5.D.166.172; 5.D.166.175; 5.D.166.240;5.D.166.244; 5.D.169.228; 5.D.169.229; 5.D.169.230; 5.D.169.231;5.D.169.236; 5.D.169.237; 5.D.169.238; 5.D.169.239; 5.D.169.154;5.D.169.157; 5.D.169.166; 5.D.169.169; 5.D.169.172; 5.D.169.175;5.D.169.240; 5.D.169.244; 5.D.172.228; 5.D.172.229; 5.D.172.230;5.D.172.231; 5.D.172.236; 5.D.172.237; 5.D.172.238; 5.D.172.239;5.D.172.154; 5.D.172.157; 5.D.172.166; 5.D.172.169; 5.D.172.172;5.D.172.175; 5.D.172.240; 5.D.172.244; 5.D.175.228; 5.D.175.229;5.D.175.230; 5.D.175.231; 5.D.175.236; 5.D.175.237; 5.D.175.238;5.D.175.239; 5.D.175.154; 5.D.175.157; 5.D.175.166; 5.D.175.169;5.D.175.172; 5.D.175.175; 5.D.175.240; 5.D.175.244; 5.D.240.228;5.D.240.229; 5.D.240.230; 5.D.240.231; 5.D.240.236; 5.D.240.237;5.D.240.238; 5.D.240.239; 5.D.240.154; 5.D.240.157; 5.D.240.166;5.D.240.169; 5.D.240.172; 5.D.240.175; 5.D.240.240; 5.D.240.244;5.D.244.228; 5.D.244.229; 5.D.244.230; 5.D.244.231; 5.D.244.236;5.D.244.237; 5.D.244.238; 5.D.244.239; 5.D.244.154; 5.D.244.157;5.D.244.166; 5.D.244.169; 5.D.244.172; 5.D.244.175; 5.D.244.240;5.D.244.244; Prodrugs of 5.E 5.E.228.228; 5.E.228.229; 5.E.228.230;5.E.228.231; 5.E.228.236; 5.E.228.237; 5.E.228.238; 5.E.228.239;5.E.228.154; 5.E.228.157; 5.E.228.166; 5.E.228.169; 5.E.228.172;5.E.228.175; 5.E.228.240; 5.E.228.244; 5.E.229.228; 5.E.229.229;5.E.229.230; 5.E.229.231; 5.E.229.236; 5.E.229.237; 5.E.229.238;5.E.229.239; 5.E.229.154; 5.E.229.157; 5.E.229.166; 5.E.229.169;5.E.229.172; 5.E.229.175; 5.E.229.240; 5.E.229.244; 5.E.230.228;5.E.230.229; 5.E.230.230; 5.E.230.231; 5.E.230.236; 5.E.230.237;5.E.230.238; 5.E.230.239; 5.E.230.154; 5.E.230.157; 5.E.230.166;5.E.230.169; 5.E.230.172; 5.E.230.175; 5.E.230.240; 5.E.230.244;5.E.231.228; 5.E.231.229; 5.E.231.230; 5.E.231.231; 5.E.231.236;5.E.231.237; 5.E.231.238; 5.E.231.239; 5.E.231.154; 5.E.231.157;5.E.231.166; 5.E.231.169; 5.E.231.172; 5.E.231.175; 5.E.231.240;5.E.231.244; 5.E.236.228; 5.E.236.229; 5.E.236.230; 5.E.236.231;5.E.236.236; 5.E.236.237; 5.E.236.238; 5.E.236.239; 5.E.236.154;5.E.236.157; 5.E.236.166; 5.E.236.169; 5.E.236.172; 5.E.236.175;5.E.236.240; 5.E.236.244; 5.E.237.228; 5.E.237.229; 5.E.237.230;5.E.237.231; 5.E.237.236; 5.E.237.237; 5.E.237.238; 5.E.237.239;5.E.237.154; 5.E.237.157; 5.E.237.166; 5.E.237.169; 5.E.237.172;5.E.237.175; 5.E.237.240; 5.E.237.244; 5.E.238.228; 5.E.238.229;5.E.238.230; 5.E.238.231; 5.E.238.236; 5.E.238.237; 5.E.238.238;5.E.238.239; 5.E.238.154; 5.E.238.157; 5.E.238.166; 5.E.238.169;5.E.238.172; 5.E.238.175; 5.E.238.240; 5.E.238.244; 5.E.239.228;5.E.239.229; 5.E.239.230; 5.E.239.231; 5.E.239.236; 5.E.239.237;5.E.239.238; 5.E.239.239; 5.E.239.154; 5.E.239.157; 5.E.239.166;5.E.239.169; 5.E.239.172; 5.E.239.175; 5.E.239.240; 5.E.239.244;5.E.154.228; 5.E.154.229; 5.E.154.230; 5.E.154.231; 5.E.154.236;5.E.154.237; 5.E.154.238; 5.E.154.239; 5.E.154.154; 5.E.154.157;5.E.154.166; 5.E.154.169; 5.E.154.172; 5.E.154.175; 5.E.154.240;5.E.154.244; 5.E.157.228; 5.E.157.229; 5.E.157.230; 5.E.157.231;5.E.157.236; 5.E.157.237; 5.E.157.238; 5.E.157.239; 5.E.157.154;5.E.157.157; 5.E.157.166; 5.E.157.169; 5.E.157.172; 5.E.157.175;5.E.157.240; 5.E.157.244; 5.E.166.228; 5.E.166.229; 5.E.166.230;5.E.166.231; 5.E.166.236; 5.E.166.237; 5.E.166.238; 5.E.166.239;5.E.166.154; 5.E.166.157; 5.E.166.166; 5.E.166.169; 5.E.166.172;5.E.166.175; 5.E.166.240; 5.E.166.244; 5.E.169.228; 5.E.169.229;5.E.169.230; 5.E.169.231; 5.E.169.236; 5.E.169.237; 5.E.169.238;5.E.169.239; 5.E.169.154; 5.E.169.157; 5.E.169.166; 5.E.169.169;5.E.169.172; 5.E.169.175; 5.E.169.240; 5.E.169.244; 5.E.172.228;5.E.172.229; 5.E.172.230; 5.E.172.231; 5.E.172.236; 5.E.172.237;5.E.172.238; 5.E.172.239; 5.E.172.154; 5.E.172.157; 5.E.172.166;5.E.172.169; 5.E.172.172; 5.E.172.175; 5.E.172.240; 5.E.172.244;5.E.175.228; 5.E.175.229; 5.E.175.230; 5.E.175.231; 5.E.175.236;5.E.175.237; 5.E.175.238; 5.E.175.239; 5.E.175.154; 5.E.175.157;5.E.175.166; 5.E.175.169; 5.E.175.172; 5.E.175.175; 5.E.175.240;5.E.175.244; 5.E.240.228; 5.E.240.229; 5.E.240.230; 5.E.240.231;5.E.240.236; 5.E.240.237; 5.E.240.238; 5.E.240.239; 5.E.240.154;5.E.240.157; 5.E.240.166; 5.E.240.169; 5.E.240.172; 5.E.240.175;5.E.240.240; 5.E.240.244; 5.E.244.228; 5.E.244.229; 5.E.244.230;5.E.244.231; 5.E.244.236; 5.E.244.237; 5.E.244.238; 5.E.244.239;5.E.244.154; 5.E.244.157; 5.E.244.166; 5.E.244.169; 5.E.244.172;5.E.244.175; 5.E.244.240; 5.E.244.244; Prodrugs of 5.G 5.G.228.228;5.G.228.229; 5.G.228.230; 5.G.228.231; 5.G.228.236; 5.G.228.237;5.G.228.238; 5.G.228.239; 5.G.228.154; 5.G.228.157; 5.G.228.166;5.G.228.169; 5.G.228.172; 5.G.228.175; 5.G.228.240; 5.G.228.244;5.G.229.228; 5.G.229.229; 5.G.229.230; 5.G.229.231; 5.G.229.236;5.G.229.237; 5.G.229.238; 5.G.229.239; 5.G.229.154; 5.G.229.157;5.G.229.166; 5.G.229.169; 5.G.229.172; 5.G.229.175; 5.G.229.240;5.G.229.244; 5.G.230.228; 5.G.230.229; 5.G.230.230; 5.G.230.231;5.G.230.236; 5.G.230.237; 5.G.230.238; 5.G.230.239; 5.G.230.154;5.G.230.157; 5.G.230.166; 5.G.230.169; 5.G.230.172; 5.G.230.175;5.G.230.240; 5.G.230.244; 5.G.231.228; 5.G.231.229; 5.G.231.230;5.G.231.231; 5.G.231.236; 5.G.231.237; 5.G.231.238; 5.G.231.239;5.G.231.154; 5.G.231.157; 5.G.231.166; 5.G.231.169; 5.G.231.172;5.G.231.175; 5.G.231.240; 5.G.231.244; 5.G.236.228; 5.G.236.229;5.G.236.230; 5.G.236.231; 5.G.236.236; 5.G.236.237; 5.G.236.238;5.G.236.239; 5.G.236.154; 5.G.236.157; 5.G.236.166; 5.G.236.169;5.G.236.172; 5.G.236.175; 5.G.236.240; 5.G.236.244; 5.G.237.228;5.G.237.229; 5.G.237.230; 5.G.237.231; 5.G.237.236; 5.G.237.237;5.G.237.238; 5.G.237.239; 5.G.237.154; 5.G.237.157; 5.G.237.166;5.G.237.169; 5.G.237.172; 5.G.237.175; 5.G.237.240; 5.G.237.244;5.G.238.228; 5.G.238.229; 5.G.238.230; 5.G.238.231; 5.G.238.236;5.G.238.237; 5.G.238.238; 5.G.238.239; 5.G.238.154; 5.G.238.157;5.G.238.166; 5.G.238.169; 5.G.238.172; 5.G.238.175; 5.G.238.240;5.G.238.244; 5.G.239.228; 5.G.239.229; 5.G.239.230; 5.G.239.231;5.G.239.236; 5.G.239.237; 5.G.239.238; 5.G.239.239; 5.G.239.154;5.G.239.157; 5.G.239.166; 5.G.239.169; 5.G.239.172; 5.G.239.175;5.G.239.240; 5.G.239.244; 5.G.154.228; 5.G.154.229; 5.G.154.230;5.G.154.231; 5.G.154.236; 5.G.154.237; 5.G.154.238; 5.G.154.239;5.G.154.154; 5.G.154.157; 5.G.154.166; 5.G.154.169; 5.G.154.172;5.G.154.175; 5.G.154.240; 5.G.154.244; 5.G.157.228; 5.G.157.229;5.G.157.230; 5.G.157.231; 5.G.157.236; 5.G.157.237; 5.G.157.238;5.G.157.239; 5.G.157.154; 5.G.157.157; 5.G.157.166; 5.G.157.169;5.G.157.172; 5.G.157.175; 5.G.157.240; 5.G.157.244; 5.G.166.228;5.G.166.229; 5.G.166.230; 5.G.166.231; 5.G.166.236; 5.G.166.237;5.G.166.238; 5.G.166.239; 5.G.166.154; 5.G.166.157; 5.G.166.166;5.G.166.169; 5.G.166.172; 5.G.166.175; 5.G.166.240; 5.G.166.244;5.G.169.228; 5.G.169.229; 5.G.169.230; 5.G.169.231; 5.G.169.236;5.G.169.237; 5.G.169.238; 5.G.169.239; 5.G.169.154; 5.G.169.157;5.G.169.166; 5.G.169.169; 5.G.169.172; 5.G.169.175; 5.G.169.240;5.G.169.244; 5.G.172.228; 5.G.172.229; 5.G.172.230; 5.G.172.231;5.G.172.236; 5.G.172.237; 5.G.172.238; 5.G.172.239; 5.G.172.154;5.G.172.157; 5.G.172.166; 5.G.172.169; 5.G.172.172; 5.G.172.175;5.G.172.240; 5.G.172.244; 5.G.175.228; 5.G.175.229; 5.G.175.230;5.G.175.231; 5.G.175.236; 5.G.175.237; 5.G.175.238; 5.G.175.239;5.G.175.154; 5.G.175.157; 5.G.175.166; 5.G.175.169; 5.G.175.172;5.G.175.175; 5.G.175.240; 5.G.175.244; 5.G.240.228; 5.G.240.229;5.G.240.230; 5.G.240.231; 5.G.240.236; 5.G.240.237; 5.G.240.238;5.G.240.239; 5.G.240.154; 5.G.240.157; 5.G.240.166; 5.G.240.169;5.G.240.172; 5.G.240.175; 5.G.240.240; 5.G.240.244; 5.G.244.228;5.G.244.229; 5.G.244.230; 5.G.244.231; 5.G.244.236; 5.G.244.237;5.G.244.238; 5.G.244.239; 5.G.244.154; 5.G.244.157; 5.G.244.166;5.G.244.169; 5.G.244.172; 5.G.244.175; 5.G.244.240; 5.G.244.244;Prodrugs of 5.I 5.I.228.228; 5.I.228.229; 5.I.228.230; 5.I.228.231;5.I.228.236; 5.I.228.237; 5.I.228.238; 5.I.228.239; 5.I.228.154;5.I.228.157; 5.I.228.166; 5.I.228.169; 5.I.228.172; 5.I.228.175;5.I.228.240; 5.I.228.244; 5.I.229.228; 5.I.229.229; 5.I.229.230;5.I.229.231; 5.I.229.236; 5.I.229.237; 5.I.229.238; 5.I.229.239;5.I.229.154; 5.I.229.157; 5.I.229.166; 5.I.229.169; 5.I.229.172;5.I.229.175; 5.I.229.240; 5.I.229.244; 5.I.230.228; 5.I.230.229;5.I.230.230; 5.I.230.231; 5.I.230.236; 5.I.230.237; 5.I.230.238;5.I.230.239; 5.I.230.154; 5.I.230.157; 5.I.230.166; 5.I.230.169;5.I.230.172; 5.I.230.175; 5.I.230.240; 5.I.230.244; 5.I.231.228;5.I.231.229; 5.I.231.230; 5.I.231.231; 5.I.231.236; 5.I.231.237;5.I.231.238; 5.I.231.239; 5.I.231.154; 5.I.231.157; 5.I.231.166;5.I.231.169; 5.I.231.172; 5.I.231.175; 5.I.231.240; 5.I.231.244;5.I.236.228; 5.I.236.229; 5.I.236.230; 5.I.236.231; 5.I.236.236;5.I.236.237; 5.I.236.238; 5.I.236.239; 5.I.236.154; 5.I.236.157;5.I.236.166; 5.I.236.169; 5.I.236.172; 5.I.236.175; 5.I.236.240;5.I.236.244; 5.I.237.228; 5.I.237.229; 5.I.237.230; 5.I.237.231;5.I.237.236; 5.I.237.237; 5.I.237.238; 5.I.237.239; 5.I.237.154;5.I.237.157; 5.I.237.166; 5.I.237.169; 5.I.237.172; 5.I.237.175;5.I.237.240; 5.I.237.244; 5.I.238.228; 5.I.238.229; 5.I.238.230;5.I.238.231; 5.I.238.236; 5.I.238.237; 5.I.238.238; 5.I.238.239;5.I.238.154; 5.I.238.157; 5.I.238.166; 5.I.238.169; 5.I.238.172;5.I.238.175; 5.I.238.240; 5.I.238.244; 5.I.239.228; 5.I.239.229;5.I.239.230; 5.I.239.231; 5.I.239.236; 5.I.239.237; 5.I.239.238;5.I.239.239; 5.I.239.154; 5.I.239.157; 5.I.239.166; 5.I.239.169;5.I.239.172; 5.I.239.175; 5.I.239.240; 5.I.239.244; 5.I.154.228;5.I.154.229; 5.I.154.230; 5.I.154.231; 5.I.154.236; 5.I.154.237;5.I.154.238; 5.I.154.239; 5.I.154.154; 5.I.154.157; 5.I.154.166;5.I.154.169; 5.I.154.172; 5.I.154.175; 5.I.154.240; 5.I.154.244;5.I.157.228; 5.I.157.229; 5.I.157.230; 5.I.157.231; 5.I.157.236;5.I.157.237; 5.I.157.238; 5.I.157.239; 5.I.157.154; 5.I.157.157;5.I.157.166; 5.I.157.169; 5.I.157.172; 5.I.157.175; 5.I.157.240;5.I.157.244; 5.I.166.228; 5.I.166.229; 5.I.166.230; 5.I.166.231;5.I.166.236; 5.I.166.237; 5.I.166.238; 5.I.166.239; 5.I.166.154;5.I.166.157; 5.I.166.166; 5.I.166.169; 5.I.166.172; 5.I.166.175;5.I.166.240; 5.I.166.244; 5.I.169.228; 5.I.169.229; 5.I.169.230;5.I.169.231; 5.I.169.236; 5.I.169.237; 5.I.169.238; 5.I.169.239;5.I.169.154; 5.I.169.157; 5.I.169.166; 5.I.169.169; 5.I.169.172;5.I.169.175; 5.I.169.240; 5.I.169.244; 5.I.172.228; 5.I.172.229;5.I.172.230; 5.I.172.231; 5.I.172.236; 5.I.172.237; 5.I.172.238;5.I.172.239; 5.I.172.154; 5.I.172.157; 5.I.172.166; 5.I.172.169;5.I.172.172; 5.I.172.175; 5.I.172.240; 5.I.172.244; 5.I.175.228;5.I.175.229; 5.I.175.230; 5.I.175.231; 5.I.175.236; 5.I.175.237;5.I.175.238; 5.I.175.239; 5.I.175.154; 5.I.175.157; 5.I.175.166;5.I.175.169; 5.I.175.172; 5.I.175.175; 5.I.175.240; 5.I.175.244;5.I.240.228; 5.I.240.229; 5.I.240.230; 5.I.240.231; 5.I.240.236;5.I.240.237; 5.I.240.238; 5.I.240.239; 5.I.240.154; 5.I.240.157;5.I.240.166; 5.I.240.169; 5.I.240.172; 5.I.240.175; 5.I.240.240;5.I.240.244; 5.I.244.228; 5.I.244.229; 5.I.244.230; 5.I.244.231;5.I.244.236; 5.I.244.237; 5.I.244.238; 5.I.244.239; 5.I.244.154;5.I.244.157; 5.I.244.166; 5.I.244.169; 5.I.244.172; 5.I.244.175;5.I.244.240; 5.I.244.244; Prodrugs of 5.J 5.J.228.228; 5.J.228.229;5.J.228.230; 5.J.228.231; 5.J.228.236; 5.J.228.237; 5.J.228.238;5.J.228.239; 5.J.228.154; 5.J.228.157; 5.J.228.166; 5.J.228.169;5.J.228.172; 5.J.228.175; 5.J.228.240; 5.J.228.244; 5.J.229.228;5.J.229.229; 5.J.229.230; 5.J.229.231; 5.J.229.236; 5.J.229.237;5.J.229.238; 5.J.229.239; 5.J.229.154; 5.J.229.157; 5.J.229.166;5.J.229.169; 5.J.229.172; 5.J.229.175; 5.J.229.240; 5.J.229.244;5.J.230.228; 5.J.230.229; 5.J.230.230; 5.J.230.231; 5.J.230.236;5.J.230.237; 5.J.230.238; 5.J.230.239; 5.J.230.154; 5.J.230.157;5.J.230.166; 5.J.230.169; 5.J.230.172; 5.J.230.175; 5.J.230.240;5.J.230.244; 5.J.231.228; 5.J.231.229; 5.J.231.230; 5.J.231.231;5.J.231.236; 5.J.231.237; 5.J.231.238; 5.J.231.239; 5.J.231.154;5.J.231.157; 5.J.231.166; 5.J.231.169; 5.J.231.172; 5.J.231.175;5.J.231.240; 5.J.231.244; 5.J.236.228; 5.J.236.229; 5.J.236.230;5.J.236.231; 5.J.236.236; 5.J.236.237; 5.J.236.238; 5.J.236.239;5.J.236.154; 5.J.236.157; 5.J.236.166; 5.J.236.169; 5.J.236.172;5.J.236.175; 5.J.236.240; 5.J.236.244; 5.J.237.228; 5.J.237.229;5.J.237.230; 5.J.237.231; 5.J.237.236; 5.J.237.237; 5.J.237.238;5.J.237.239; 5.J.237.154; 5.J.237.157; 5.J.237.166; 5.J.237.169;5.J.237.172; 5.J.237.175; 5.J.237.240; 5.J.237.244; 5.J.238.228;5.J.238.229; 5.J.238.230; 5.J.238.231; 5.J.238.236; 5.J.238.237;5.J.238.238; 5.J.238.239; 5.J.238.154; 5.J.238.157; 5.J.238.166;5.J.238.169; 5.J.238.172; 5.J.238.175; 5.J.238.240; 5.J.238.244;5.J.239.228; 5.J.239.229; 5.J.239.230; 5.J.239.231; 5.J.239.236;5.J.239.237; 5.J.239.238; 5.J.239.239; 5.J.239.154; 5.J.239.157;5.J.239.166; 5.J.239.169; 5.J.239.172; 5.J.239.175; 5.J.239.240;5.J.239.244; 5.J.154.228; 5.J.154.229; 5.J.154.230; 5.J.154.231;5.J.154.236; 5.J.154.237; 5.J.154.238; 5.J.154.239; 5.J.154.154;5.J.154.157; 5.J.154.166; 5.J.154.169; 5.J.154.172; 5.J.154.175;5.J.154.240; 5.J.154.244; 5.J.157.228; 5.J.157.229; 5.J.157.230;5.J.157.231; 5.J.157.236; 5.J.157.237; 5.J.157.238; 5.J.157.239;5.J.157.154; 5.J.157.157; 5.J.157.166; 5.J.157.169; 5.J.157.172;5.J.157.175; 5.J.157.240; 5.J.157.244; 5.J.166.228; 5.J.166.229;5.J.166.230; 5.J.166.231; 5.J.166.236; 5.J.166.237; 5.J.166.238;5.J.166.239; 5.J.166.154; 5.J.166.157; 5.J.166.166; 5.J.166.169;5.J.166.172; 5.J.166.175; 5.J.166.240; 5.J.166.244; 5.J.169.228;5.J.169.229; 5.J.169.230; 5.J.169.231; 5.J.169.236; 5.J.169.237;5.J.169.238; 5.J.169.239; 5.J.169.154; 5.J.169.157; 5.J.169.166;5.J.169.169; 5.J.169.172; 5.J.169.175; 5.J.169.240; 5.J.169.244;5.J.172.228; 5.J.172.229; 5.J.172.230; 5.J.172.231; 5.J.172.236;5.J.172.237; 5.J.172.238; 5.J.172.239; 5.J.172.154; 5.J.172.157;5.J.172.166; 5.J.172.169; 5.J.172.172; 5.J.172.175; 5.J.172.240;5.J.172.244; 5.J.175.228; 5.J.175.229; 5.J.175.230; 5.J.175.231;5.J.175.236; 5.J.175.237; 5.J.175.238; 5.J.175.239; 5.J.175.154;5.J.175.157; 5.J.175.166; 5.J.175.169; 5.J.175.172; 5.J.175.175;5.J.175.240; 5.J.175.244; 5.J.240.228; 5.J.240.229; 5.J.240.230;5.J.240.231; 5.J.240.236; 5.J.240.237; 5.J.240.238; 5.J.240.239;5.J.240.154; 5.J.240.157; 5.J.240.166; 5.J.240.169; 5.J.240.172;5.J.240.175; 5.J.240.240; 5.J.240.244; 5.J.244.228; 5.J.244.229;5.J.244.230; 5.J.244.231; 5.J.244.236; 5.J.244.237; 5.J.244.238;5.J.244.239; 5.J.244.154; 5.J.244.157; 5.J.244.166; 5.J.244.169;5.J.244.172; 5.J.244.175; 5.J.244.240; 5.J.244.244; Prodrugs of 5.L5.L.228.228; 5.L.228.229; 5.L.228.230; 5.L.228.231; 5.L.228.236;5.L.228.237; 5.L.228.238; 5.L.228.239; 5.L.228.154; 5.L.228.157;5.L.228.166; 5.L.228.169; 5.L.228.172; 5.L.228.175; 5.L.228.240;5.L.228.244; 5.L.229.228; 5.L.229.229; 5.L.229.230; 5.L.229.231;5.L.229.236; 5.L.229.237; 5.L.229.238; 5.L.229.239; 5.L.229.154;5.L.229.157; 5.L.229.166; 5.L.229.169; 5.L.229.172; 5.L.229.175;5.L.229.240; 5.L.229.244; 5.L.230.228; 5.L.230.229; 5.L.230.230;5.L.230.231; 5.L.230.236; 5.L.230.237; 5.L.230.238; 5.L.230.239;5.L.230.154; 5.L.230.157; 5.L.230.166; 5.L.230.169; 5.L.230.172;5.L.230.175; 5.L.230.240; 5.L.230.244; 5.L.231.228; 5.L.231.229;5.L.231.230; 5.L.231.231; 5.L.231.236; 5.L.231.237; 5.L.231.238;5.L.231.239; 5.L.231.154; 5.L.231.157; 5.L.231.166; 5.L.231.169;5.L.231.172; 5.L.231.175; 5.L.231.240; 5.L.231.244; 5.L.236.228;5.L.236.229; 5.L.236.230; 5.L.236.231; 5.L.236.236; 5.L.236.237;5.L.236.238; 5.L.236.239; 5.L.236.154; 5.L.236.157; 5.L.236.166;5.L.236.169; 5.L.236.172; 5.L.236.175; 5.L.236.240; 5.L.236.244;5.L.237.228; 5.L.237.229; 5.L.237.230; 5.L.237.231; 5.L.237.236;5.L.237.237; 5.L.237.238; 5.L.237.239; 5.L.237.154; 5.L.237.157;5.L.237.166; 5.L.237.169; 5.L.237.172; 5.L.237.175; 5.L.237.240;5.L.237.244; 5.L.238.228; 5.L.238.229; 5.L.238.230; 5.L.238.231;5.L.238.236; 5.L.238.237; 5.L.238.238; 5.L.238.239; 5.L.238.154;5.L.238.157; 5.L.238.166; 5.L.238.169; 5.L.238.172; 5.L.238.175;5.L.238.240; 5.L.238.244; 5.L.239.228; 5.L.239.229; 5.L.239.230;5.L.239.231; 5.L.239.236; 5.L.239.237; 5.L.239.238; 5.L.239.239;5.L.239.154; 5.L.239.157; 5.L.239.166; 5.L.239.169; 5.L.239.172;5.L.239.175; 5.L.239.240; 5.L.239.244; 5.L.154.228; 5.L.154.229;5.L.154.230; 5.L.154.231; 5.L.154.236; 5.L.154.237; 5.L.154.238;5.L.154.239; 5.L.154.154; 5.L.154.157; 5.L.154.166; 5.L.154.169;5.L.154.172; 5.L.154.175; 5.L.154.240; 5.L.154.244; 5.L.157.228;5.L.157.229; 5.L.157.230; 5.L.157.231; 5.L.157.236; 5.L.157.237;5.L.157.238; 5.L.157.239; 5.L.157.154; 5.L.157.157; 5.L.157.166;5.L.157.169; 5.L.157.172; 5.L.157.175; 5.L.157.240; 5.L.157.244;5.L.166.228; 5.L.166.229; 5.L.166.230; 5.L.166.231; 5.L.166.236;5.L.166.237; 5.L.166.238; 5.L.166.239; 5.L.166.154; 5.L.166.157;5.L.166.166; 5.L.166.169; 5.L.166.172; 5.L.166.175; 5.L.166.240;5.L.166.244; 5.L.169.228; 5.L.169.229; 5.L.169.230; 5.L.169.231;5.L.169.236; 5.L.169.237; 5.L.169.238; 5.L.169.239; 5.L.169.154;5.L.169.157; 5.L.169.166; 5.L.169.169; 5.L.169.172; 5.L.169.175;5.L.169.240; 5.L.169.244; 5.L.172.228; 5.L.172.229; 5.L.172.230;5.L.172.231; 5.L.172.236; 5.L.172.237; 5.L.172.238; 5.L.172.239;5.L.172.154; 5.L.172.157; 5.L.172.166; 5.L.172.169; 5.L.172.172;5.L.172.175; 5.L.172.240; 5.L.172.244; 5.L.175.228; 5.L.175.229;5.L.175.230; 5.L.175.231; 5.L.175.236; 5.L.175.237; 5.L.175.238;5.L.175.239; 5.L.175.154; 5.L.175.157; 5.L.175.166; 5.L.175.169;5.L.175.172; 5.L.175.175; 5.L.175.240; 5.L.175.244; 5.L.240.228;5.L.240.229; 5.L.240.230; 5.L.240.231; 5.L.240.236; 5.L.240.237;5.L.240.238; 5.L.240.239; 5.L.240.154; 5.L.240.157; 5.L.240.166;5.L.240.169; 5.L.240.172; 5.L.240.175; 5.L.240.240; 5.L.240.244;5.L.244.228; 5.L.244.229; 5.L.244.230; 5.L.244.231; 5.L.244.236;5.L.244.237; 5.L.244.238; 5.L.244.239; 5.L.244.154; 5.L.244.157;5.L.244.166; 5.L.244.169; 5.L.244.172; 5.L.244.175; 5.L.244.240;5.L.244.244; Prodrugs of 5.O 5.O.228.228; 5.O.228.229; 5.O.228.230;5.O.228.231; 5.O.228.236; 5.O.228.237; 5.O.228.238; 5.O.228.239;5.O.228.154; 5.O.228.157; 5.O.228.166; 5.O.228.169; 5.O.228.172;5.O.228.175; 5.O.228.240; 5.O.228.244; 5.O.229.228; 5.O.229.229;5.O.229.230; 5.O.229.231; 5.O.229.236; 5.O.229.237; 5.O.229.238;5.O.229.239; 5.O.229.154; 5.O.229.157; 5.O.229.166; 5.O.229.169;5.O.229.172; 5.O.229.175; 5.O.229.240; 5.O.229.244; 5.O.230.228;5.O.230.229; 5.O.230.230; 5.O.230.231; 5.O.230.236; 5.O.230.237;5.O.230.238; 5.O.230.239; 5.O.230.154; 5.O.230.157; 5.O.230.166;5.O.230.169; 5.O.230.172; 5.O.230.175; 5.O.230.240; 5.O.230.244;5.O.231.228; 5.O.231.229; 5.O.231.230; 5.O.231.231; 5.O.231.236;5.O.231.237; 5.O.231.238; 5.O.231.239; 5.O.231.154; 5.O.231.157;5.O.231.166; 5.O.231.169; 5.O.231.172; 5.O.231.175; 5.O.231.240;5.O.231.244; 5.O.236.228; 5.O.236.229; 5.O.236.230; 5.O.236.231;5.O.236.236; 5.O.236.237; 5.O.236.238; 5.O.236.239; 5.O.236.154;5.O.236.157; 5.O.236.166; 5.O.236.169; 5.O.236.172; 5.O.236.175;5.O.236.240; 5.O.236.244; 5.O.237.228; 5.O.237.229; 5.O.237.230;5.O.237.231; 5.O.237.236; 5.O.237.237; 5.O.237.238; 5.O.237.239;5.O.237.154; 5.O.237.157; 5.O.237.166; 5.O.237.169; 5.O.237.172;5.O.237.175; 5.O.237.240; 5.O.237.244; 5.O.238.228; 5.O.238.229;5.O.238.230; 5.O.238.231; 5.O.238.236; 5.O.238.237; 5.O.238.238;5.O.238.239; 5.O.238.154; 5.O.238.157; 5.O.238.166; 5.O.238.169;5.O.238.172; 5.O.238.175; 5.O.238.240; 5.O.238.244; 5.O.239.228;5.O.239.229; 5.O.239.230; 5.O.239.231; 5.O.239.236; 5.O.239.237;5.O.239.238; 5.O.239.239; 5.O.239.154; 5.O.239.157; 5.O.239.166;5.O.239.169; 5.O.239.172; 5.O.239.175; 5.O.239.240; 5.O.239.244;5.O.154.228; 5.O.154.229; 5.O.154.230; 5.O.154.231; 5.O.154.236;5.O.154.237; 5.O.154.238; 5.O.154.239; 5.O.154.154; 5.O.154.157;5.O.154.166; 5.O.154.169; 5.O.154.172; 5.O.154.175; 5.O.154.240;5.O.154.244; 5.O.157.228; 5.O.157.229; 5.O.157.230; 5.O.157.231;5.O.157.236; 5.O.157.237; 5.O.157.238; 5.O.157.239; 5.O.157.154;5.O.157.157; 5.O.157.166; 5.O.157.169; 5.O.157.172; 5.O.157.175;5.O.157.240; 5.O.157.244; 5.O.166.228; 5.O.166.229; 5.O.166.230;5.O.166.231; 5.O.166.236; 5.O.166.237; 5.O.166.238; 5.O.166.239;5.O.166.154; 5.O.166.157; 5.O.166.166; 5.O.166.169; 5.O.166.172;5.O.166.175; 5.O.166.240; 5.O.166.244; 5.O.169.228; 5.O.169.229;5.O.169.230; 5.O.169.231; 5.O.169.236; 5.O.169.237; 5.O.169.238;5.O.169.239; 5.O.169.154; 5.O.169.157; 5.O.169.166; 5.O.169.169;5.O.169.172; 5.O.169.175; 5.O.169.240; 5.O.169.244; 5.O.172.228;5.O.172.229; 5.O.172.230; 5.O.172.231; 5.O.172.236; 5.O.172.237;5.O.172.238; 5.O.172.239; 5.O.172.154; 5.O.172.157; 5.O.172.166;5.O.172.169; 5.O.172.172; 5.O.172.175; 5.O.172.240; 5.O.172.244;5.O.175.228; 5.O.175.229; 5.O.175.230; 5.O.175.231; 5.O.175.236;5.O.175.237; 5.O.175.238; 5.O.175.239; 5.O.175.154; 5.O.175.157;5.O.175.166; 5.O.175.169; 5.O.175.172; 5.O.175.175; 5.O.175.240;5.O.175.244; 5.O.240.228; 5.O.240.229; 5.O.240.230; 5.O.240.231;5.O.240.236; 5.O.240.237; 5.O.240.238; 5.O.240.239; 5.O.240.154;5.O.240.157; 5.O.240.166; 5.O.240.169; 5.O.240.172; 5.O.240.175;5.O.240.240; 5.O.240.244; 5.O.244.228; 5.O.244.229; 5.O.244.230;5.O.244.231; 5.O.244.236; 5.O.244.237; 5.O.244.238; 5.O.244.239;5.O.244.154; 5.O.244.157; 5.O.244.166; 5.O.244.169; 5.O.244.172;5.O.244.175; 5.O.244.240; 5.O.244.244; Prodrugs of 5.P 5.P.228.228;5.P.228.229; 5.P.228.230; 5.P.228.231; 5.P.228.236; 5.P.228.237;5.P.228.238; 5.P.228.239; 5.P.228.154; 5.P.228.157; 5.P.228.166;5.P.228.169; 5.P.228.172; 5.P.228.175; 5.P.228.240; 5.P.228.244;5.P.229.228; 5.P.229.229; 5.P.229.230; 5.P.229.231; 5.P.229.236;5.P.229.237; 5.P.229.238; 5.P.229.239; 5.P.229.154; 5.P.229.157;5.P.229.166; 5.P.229.169; 5.P.229.172; 5.P.229.175; 5.P.229.240;5.P.229.244; 5.P.230.228; 5.P.230.229; 5.P.230.230; 5.P.230.231;5.P.230.236; 5.P.230.237; 5.P.230.238; 5.P.230.239; 5.P.230.154;5.P.230.157; 5.P.230.166; 5.P.230.169; 5.P.230.172; 5.P.230.175;5.P.230.240; 5.P.230.244; 5.P.231.228; 5.P.231.229; 5.P.231.230;5.P.231.231; 5.P.231.236; 5.P.231.237; 5.P.231.238; 5.P.231.239;5.P.231.154; 5.P.231.157; 5.P.231.166; 5.P.231.169; 5.P.231.172;5.P.231.175; 5.P.231.240; 5.P.231.244; 5.P.236.228; 5.P.236.229;5.P.236.230; 5.P.236.231; 5.P.236.236; 5.P.236.237; 5.P.236.238;5.P.236.239; 5.P.236.154; 5.P.236.157; 5.P.236.166; 5.P.236.169;5.P.236.172; 5.P.236.175; 5.P.236.240; 5.P.236.244; 5.P.237.228;5.P.237.229; 5.P.237.230; 5.P.237.231; 5.P.237.236; 5.P.237.237;5.P.237.238; 5.P.237.239; 5.P.237.154; 5.P.237.157; 5.P.237.166;5.P.237.169; 5.P.237.172; 5.P.237.175; 5.P.237.240; 5.P.237.244;5.P.238.228; 5.P.238.229; 5.P.238.230; 5.P.238.231; 5.P.238.236;5.P.238.237; 5.P.238.238; 5.P.238.239; 5.P.238.154; 5.P.238.157;5.P.238.166; 5.P.238.169; 5.P.238.172; 5.P.238.175; 5.P.238.240;5.P.238.244; 5.P.239.228; 5.P.239.229; 5.P.239.230; 5.P.239.231;5.P.239.236; 5.P.239.237; 5.P.239.238; 5.P.239.239; 5.P.239.154;5.P.239.157; 5.P.239.166; 5.P.239.169; 5.P.239.172; 5.P.239.175;5.P.239.240; 5.P.239.244; 5.P.154.228; 5.P.154.229; 5.P.154.230;5.P.154.231; 5.P.154.236; 5.P.154.237; 5.P.154.238; 5.P.154.239;5.P.154.154; 5.P.154.157; 5.P.154.166; 5.P.154.169; 5.P.154.172;5.P.154.175; 5.P.154.240; 5.P.154.244; 5.P.157.228; 5.P.157.229;5.P.157.230; 5.P.157.231; 5.P.157.236; 5.P.157.237; 5.P.157.238;5.P.157.239; 5.P.157.154; 5.P.157.157; 5.P.157.166; 5.P.157.169;5.P.157.172; 5.P.157.175; 5.P.157.240; 5.P.157.244; 5.P.166.228;5.P.166.229; 5.P.166.230; 5.P.166.231; 5.P.166.236; 5.P.166.237;5.P.166.238; 5.P.166.239; 5.P.166.154; 5.P.166.157; 5.P.166.166;5.P.166.169; 5.P.166.172; 5.P.166.175; 5.P.166.240; 5.P.166.244;5.P.169.228; 5.P.169.229; 5.P.169.230; 5.P.169.231; 5.P.169.236;5.P.169.237; 5.P.169.238; 5.P.169.239; 5.P.169.154; 5.P.169.157;5.P.169.166; 5.P.169.169; 5.P.169.172; 5.P.169.175; 5.P.169.240;5.P.169.244; 5.P.172.228; 5.P.172.229; 5.P.172.230; 5.P.172.231;5.P.172.236; 5.P.172.237; 5.P.172.238; 5.P.172.239; 5.P.172.154;5.P.172.157; 5.P.172.166; 5.P.172.169; 5.P.172.172; 5.P.172.175;5.P.172.240; 5.P.172.244; 5.P.175.228; 5.P.175.229; 5.P.175.230;5.P.175.231; 5.P.175.236; 5.P.175.237; 5.P.175.238; 5.P.175.239;5.P.175.154; 5.P.175.157; 5.P.175.166; 5.P.175.169; 5.P.175.172;5.P.175.175; 5.P.175.240; 5.P.175.244; 5.P.240.228; 5.P.240.229;5.P.240.230; 5.P.240.231; 5.P.240.236; 5.P.240.237; 5.P.240.238;5.P.240.239; 5.P.240.154; 5.P.240.157; 5.P.240.166; 5.P.240.169;5.P.240.172; 5.P.240.175; 5.P.240.240; 5.P.240.244; 5.P.244.228;5.P.244.229; 5.P.244.230; 5.P.244.231; 5.P.244.236; 5.P.244.237;5.P.244.238; 5.P.244.239; 5.P.244.154; 5.P.244.157; 5.P.244.166;5.P.244.169; 5.P.244.172; 5.P.244.175; 5.P.244.240; 5.P.244.244;Prodrugs of 5.U 5.U.228.228; 5.U.228.229; 5.U.228.230; 5.U.228.231;5.U.228.236; 5.U.228.237; 5.U.228.238; 5.U.228.239; 5.U.228.154;5.U.228.157; 5.U.228.166; 5.U.228.169; 5.U.228.172; 5.U.228.175;5.U.228.240; 5.U.228.244; 5.U.229.228; 5.U.229.229; 5.U.229.230;5.U.229.231; 5.U.229.236; 5.U.229.237; 5.U.229.238; 5.U.229.239;5.U.229.154; 5.U.229.157; 5.U.229.166; 5.U.229.169; 5.U.229.172;5.U.229.175; 5.U.229.240; 5.U.229.244; 5.U.230.228; 5.U.230.229;5.U.230.230; 5.U.230.231; 5.U.230.236; 5.U.230.237; 5.U.230.238;5.U.230.239; 5.U.230.154; 5.U.230.157; 5.U.230.166; 5.U.230.169;5.U.230.172; 5.U.230.175; 5.U.230.240; 5.U.230.244; 5.U.231.228;5.U.231.229; 5.U.231.230; 5.U.231.231; 5.U.231.236; 5.U.231.237;5.U.231.238; 5.U.231.239; 5.U.231.154; 5.U.231.157; 5.U.231.166;5.U.231.169; 5.U.231.172; 5.U.231.175; 5.U.231.240; 5.U.231.244;5.U.236.228; 5.U.236.229; 5.U.236.230; 5.U.236.231; 5.U.236.236;5.U.236.237; 5.U.236.238; 5.U.236.239; 5.U.236.154; 5.U.236.157;5.U.236.166; 5.U.236.169; 5.U.236.172; 5.U.236.175; 5.U.236.240;5.U.236.244; 5.U.237.228; 5.U.237.229; 5.U.237.230; 5.U.237.231;5.U.237.236; 5.U.237.237; 5.U.237.238; 5.U.237.239; 5.U.237.154;5.U.237.157; 5.U.237.166; 5.U.237.169; 5.U.237.172; 5.U.237.175;5.U.237.240; 5.U.237.244; 5.U.238.228; 5.U.238.229; 5.U.238.230;5.U.238.231; 5.U.238.236; 5.U.238.237; 5.U.238.238; 5.U.238.239;5.U.238.154; 5.U.238.157; 5.U.238.166; 5.U.238.169; 5.U.238.172;5.U.238.175; 5.U.238.240; 5.U.238.244; 5.U.239.228; 5.U.239.229;5.U.239.230; 5.U.239.231; 5.U.239.236; 5.U.239.237; 5.U.239.238;5.U.239.239; 5.U.239.154; 5.U.239.157; 5.U.239.166; 5.U.239.169;5.U.239.172; 5.U.239.175; 5.U.239.240; 5.U.239.244; 5.U.154.228;5.U.154.229; 5.U.154.230; 5.U.154.231; 5.U.154.236; 5.U.154.237;5.U.154.238; 5.U.154.239; 5.U.154.154; 5.U.154.157; 5.U.154.166;5.U.154.169; 5.U.154.172; 5.U.154.175; 5.U.154.240; 5.U.154.244;5.U.157.228; 5.U.157.229; 5.U.157.230; 5.U.157.231; 5.U.157.236;5.U.157.237; 5.U.157.238; 5.U.157.239; 5.U.157.154; 5.U.157.157;5.U.157.166; 5.U.157.169; 5.U.157.172; 5.U.157.175; 5.U.157.240;5.U.157.244; 5.U.166.228; 5.U.166.229; 5.U.166.230; 5.U.166.231;5.U.166.236; 5.U.166.237; 5.U.166.238; 5.U.166.239; 5.U.166.154;5.U.166.157; 5.U.166.166; 5.U.166.169; 5.U.166.172; 5.U.166.175;5.U.166.240; 5.U.166.244; 5.U.169.228; 5.U.169.229; 5.U.169.230;5.U.169.231; 5.U.169.236; 5.U.169.237; 5.U.169.238; 5.U.169.239;5.U.169.154; 5.U.169.157; 5.U.169.166; 5.U.169.169; 5.U.169.172;5.U.169.175; 5.U.169.240; 5.U.169.244; 5.U.172.228; 5.U.172.229;5.U.172.230; 5.U.172.231; 5.U.172.236; 5.U.172.237; 5.U.172.238;5.U.172.239; 5.U.172.154; 5.U.172.157; 5.U.172.166; 5.U.172.169;5.U.172.172; 5.U.172.175; 5.U.172.240; 5.U.172.244; 5.U.175.228;5.U.175.229; 5.U.175.230; 5.U.175.231; 5.U.175.236; 5.U.175.237;5.U.175.238; 5.U.175.239; 5.U.175.154; 5.U.175.157; 5.U.175.166;5.U.175.169; 5.U.175.172; 5.U.175.175; 5.U.175.240; 5.U.175.244;5.U.240.228; 5.U.240.229; 5.U.240.230; 5.U.240.231; 5.U.240.236;5.U.240.237; 5.U.240.238; 5.U.240.239; 5.U.240.154; 5.U.240.157;5.U.240.166; 5.U.240.169; 5.U.240.172; 5.U.240.175; 5.U.240.240;5.U.240.244; 5.U.244.228; 5.U.244.229; 5.U.244.230; 5.U.244.231;5.U.244.236; 5.U.244.237; 5.U.244.238; 5.U.244.239; 5.U.244.154;5.U.244.157; 5.U.244.166; 5.U.244.169; 5.U.244.172; 5.U.244.175;5.U.244.240; 5.U.244.244; Prodrugs of 5.W 5.W.228.228; 5.W.228.229;5.W.228.230; 5.W.228.231; 5.W.228.236; 5.W.228.237; 5.W.228.238;5.W.228.239; 5.W.228.154; 5.W.228.157; 5.W.228.166; 5.W.228.169;5.W.228.172; 5.W.228.175; 5.W.228.240; 5.W.228.244; 5.W.229.228;5.W.229.229; 5.W.229.230; 5.W.229.231; 5.W.229.236; 5.W.229.237;5.W.229.238; 5.W.229.239; 5.W.229.154; 5.W.229.157; 5.W.229.166;5.W.229.169; 5.W.229.172; 5.W.229.175; 5.W.229.240; 5.W.229.244;5.W.230.228; 5.W.230.229; 5.W.230.230; 5.W.230.231; 5.W.230.236;5.W.230.237; 5.W.230.238; 5.W.230.239; 5.W.230.154; 5.W.230.157;5.W.230.166; 5.W.230.169; 5.W.230.172; 5.W.230.175; 5.W.230.240;5.W.230.244; 5.W.231.228; 5.W.231.229; 5.W.231.230; 5.W.231.231;5.W.231.236; 5.W.231.237; 5.W.231.238; 5.W.231.239; 5.W.231.154;5.W.231.157; 5.W.231.166; 5.W.231.169; 5.W.231.172; 5.W.231.175;5.W.231.240; 5.W.231.244; 5.W.236.228; 5.W.236.229; 5.W.236.230;5.W.236.231; 5.W.236.236; 5.W.236.237; 5.W.236.238; 5.W.236.239;5.W.236.154; 5.W.236.157; 5.W.236.166; 5.W.236.169; 5.W.236.172;5.W.236.175; 5.W.236.240; 5.W.236.244; 5.W.237.228; 5.W.237.229;5.W.237.230; 5.W.237.231; 5.W.237.236; 5.W.237.237; 5.W.237.238;5.W.237.239; 5.W.237.154; 5.W.237.157; 5.W.237.166; 5.W.237.169;5.W.237.172; 5.W.237.175; 5.W.237.240; 5.W.237.244; 5.W.238.228;5.W.238.229; 5.W.238.230; 5.W.238.231; 5.W.238.236; 5.W.238.237;5.W.238.238; 5.W.238.239; 5.W.238.154; 5.W.238.157; 5.W.238.166;5.W.238.169; 5.W.238.172; 5.W.238.175; 5.W.238.240; 5.W.238.244;5.W.239.228; 5.W.239.229; 5.W.239.230; 5.W.239.231; 5.W.239.236;5.W.239.237; 5.W.239.238; 5.W.239.239; 5.W.239.154; 5.W.239.157;5.W.239.166; 5.W.239.169; 5.W.239.172; 5.W.239.175; 5.W.239.240;5.W.239.244; 5.W.154.228; 5.W.154.229; 5.W.154.230; 5.W.154.231;5.W.154.236; 5.W.154.237; 5.W.154.238; 5.W.154.239; 5.W.154.154;5.W.154.157; 5.W.154.166; 5.W.154.169; 5.W.154.172; 5.W.154.175;5.W.154.240; 5.W.154.244; 5.W.157.228; 5.W.157.229; 5.W.157.230;5.W.157.231; 5.W.157.236; 5.W.157.237; 5.W.157.238; 5.W.157.239;5.W.157.154; 5.W.157.157; 5.W.157.166; 5.W.157.169; 5.W.157.172;5.W.157.175; 5.W.157.240; 5.W.157.244; 5.W.166.228; 5.W.166.229;5.W.166.230; 5.W.166.231; 5.W.166.236; 5.W.166.237; 5.W.166.238;5.W.166.239; 5.W.166.154; 5.W.166.157; 5.W.166.166; 5.W.166.169;5.W.166.172; 5.W.166.175; 5.W.166.240; 5.W.166.244; 5.W.169.228;5.W.169.229; 5.W.169.230; 5.W.169.231; 5.W.169.236; 5.W.169.237;5.W.169.238; 5.W.169.239; 5.W.169.154; 5.W.169.157; 5.W.169.166;5.W.169.169; 5.W.169.172; 5.W.169.175; 5.W.169.240; 5.W.169.244;5.W.172.228; 5.W.172.229; 5.W.172.230; 5.W.172.231; 5.W.172.236;5.W.172.237; 5.W.172.238; 5.W.172.239; 5.W.172.154; 5.W.172.157;5.W.172.166; 5.W.172.169; 5.W.172.172; 5.W.172.175; 5.W.172.240;5.W.172.244; 5.W.175.228; 5.W.175.229; 5.W.175.230; 5.W.175.231;5.W.175.236; 5.W.175.237; 5.W.175.238; 5.W.175.239; 5.W.175.154;5.W.175.157; 5.W.175.166; 5.W.175.169; 5.W.175.172; 5.W.175.175;5.W.175.240; 5.W.175.244; 5.W.240.228; 5.W.240.229; 5.W.240.230;5.W.240.231; 5.W.240.236; 5.W.240.237; 5.W.240.238; 5.W.240.239;5.W.240.154; 5.W.240.157; 5.W.240.166; 5.W.240.169; 5.W.240.172;5.W.240.175; 5.W.240.240; 5.W.240.244; 5.W.244.228; 5.W.244.229;5.W.244.230; 5.W.244.231; 5.W.244.236; 5.W.244.237; 5.W.244.238;5.W.244.239; 5.W.244.154; 5.W.244.157; 5.W.244.166; 5.W.244.169;5.W.244.172; 5.W.244.175; 5.W.244.240; 5.W.244.244; Prodrugs of 5.Y5.Y.228.228; 5.Y.228.229; 5.Y.228.230; 5.Y.228.231; 5.Y.228.236;5.Y.228.237; 5.Y.228.238; 5.Y.228.239; 5.Y.228.154; 5.Y.228.157;5.Y.228.166; 5.Y.228.169; 5.Y.228.172; 5.Y.228.175; 5.Y.228.240;5.Y.228.244; 5.Y.229.228; 5.Y.229.229; 5.Y.229.230; 5.Y.229.231;5.Y.229.236; 5.Y.229.237; 5.Y.229.238; 5.Y.229.239; 5.Y.229.154;5.Y.229.157; 5.Y.229.166; 5.Y.229.169; 5.Y.229.172; 5.Y.229.175;5.Y.229.240; 5.Y.229.244; 5.Y.230.228; 5.Y.230.229; 5.Y.230.230;5.Y.230.231; 5.Y.230.236; 5.Y.230.237; 5.Y.230.238; 5.Y.230.239;5.Y.230.154; 5.Y.230.157; 5.Y.230.166; 5.Y.230.169; 5.Y.230.172;5.Y.230.175; 5.Y.230.240; 5.Y.230.244; 5.Y.231.228; 5.Y.231.229;5.Y.231.230; 5.Y.231.231; 5.Y.231.236; 5.Y.231.237; 5.Y.231.238;5.Y.231.239; 5.Y.231.154; 5.Y.231.157; 5.Y.231.166; 5.Y.231.169;5.Y.231.172; 5.Y.231.175; 5.Y.231.240; 5.Y.231.244; 5.Y.236.228;5.Y.236.229; 5.Y.236.230; 5.Y.236.231; 5.Y.236.236; 5.Y.236.237;5.Y.236.238; 5.Y.236.239; 5.Y.236.154; 5.Y.236.157; 5.Y.236.166;5.Y.236.169; 5.Y.236.172; 5.Y.236.175; 5.Y.236.240; 5.Y.236.244;5.Y.237.228; 5.Y.237.229; 5.Y.237.230; 5.Y.237.231; 5.Y.237.236;5.Y.237.237; 5.Y.237.238; 5.Y.237.239; 5.Y.237.154; 5.Y.237.157;5.Y.237.166; 5.Y.237.169; 5.Y.237.172; 5.Y.237.175; 5.Y.237.240;5.Y.237.244; 5.Y.238.228; 5.Y.238.229; 5.Y.238.230; 5.Y.238.231;5.Y.238.236; 5.Y.238.237; 5.Y.238.238; 5.Y.238.239; 5.Y.238.154;5.Y.238.157; 5.Y.238.166; 5.Y.238.169; 5.Y.238.172; 5.Y.238.175;5.Y.238.240; 5.Y.238.244; 5.Y.239.228; 5.Y.239.229; 5.Y.239.230;5.Y.239.231; 5.Y.239.236; 5.Y.239.237; 5.Y.239.238; 5.Y.239.239;5.Y.239.154; 5.Y.239.157; 5.Y.239.166; 5.Y.239.169; 5.Y.239.172;5.Y.239.175; 5.Y.239.240; 5.Y.239.244; 5.Y.154.228; 5.Y.154.229;5.Y.154.230; 5.Y.154.231; 5.Y.154.236; 5.Y.154.237; 5.Y.154.238;5.Y.154.239; 5.Y.154.154; 5.Y.154.157; 5.Y.154.166; 5.Y.154.169;5.Y.154.172; 5.Y.154.175; 5.Y.154.240; 5.Y.154.244; 5.Y.157.228;5.Y.157.229; 5.Y.157.230; 5.Y.157.231; 5.Y.157.236; 5.Y.157.237;5.Y.157.238; 5.Y.157.239; 5.Y.157.154; 5.Y.157.157; 5.Y.157.166;5.Y.157.169; 5.Y.157.172; 5.Y.157.175; 5.Y.157.240; 5.Y.157.244;5.Y.166.228; 5.Y.166.229; 5.Y.166.230; 5.Y.166.231; 5.Y.166.236;5.Y.166.237; 5.Y.166.238; 5.Y.166.239; 5.Y.166.154; 5.Y.166.157;5.Y.166.166; 5.Y.166.169; 5.Y.166.172; 5.Y.166.175; 5.Y.166.240;5.Y.166.244; 5.Y.169.228; 5.Y.169.229; 5.Y.169.230; 5.Y.169.231;5.Y.169.236; 5.Y.169.237; 5.Y.169.238; 5.Y.169.239; 5.Y.169.154;5.Y.169.157; 5.Y.169.166; 5.Y.169.169; 5.Y.169.172; 5.Y.169.175;5.Y.169.240; 5.Y.169.244; 5.Y.172.228; 5.Y.172.229; 5.Y.172.230;5.Y.172.231; 5.Y.172.236; 5.Y.172.237; 5.Y.172.238; 5.Y.172.239;5.Y.172.154; 5.Y.172.157; 5.Y.172.166; 5.Y.172.169; 5.Y.172.172;5.Y.172.175; 5.Y.172.240; 5.Y.172.244; 5.Y.175.228; 5.Y.175.229;5.Y.175.230; 5.Y.175.231; 5.Y.175.236; 5.Y.175.237; 5.Y.175.238;5.Y.175.239; 5.Y.175.154; 5.Y.175.157; 5.Y.175.166; 5.Y.175.169;5.Y.175.172; 5.Y.175.175; 5.Y.175.240; 5.Y.175.244; 5.Y.240.228;5.Y.240.229; 5.Y.240.230; 5.Y.240.231; 5.Y.240.236; 5.Y.240.237;5.Y.240.238; 5.Y.240.239; 5.Y.240.154; 5.Y.240.157; 5.Y.240.166;5.Y.240.169; 5.Y.240.172; 5.Y.240.175; 5.Y.240.240; 5.Y.240.244;5.Y.244.228; 5.Y.244.229; 5.Y.244.230; 5.Y.244.231; 5.Y.244.236;5.Y.244.237; 5.Y.244.238; 5.Y.244.239; 5.Y.244.154; 5.Y.244.157;5.Y.244.166; 5.Y.244.169; 5.Y.244.172; 5.Y.244.175; 5.Y.244.240;5.Y.244.244; Prodrugs of 6.B 6.B.228.228; 6.B.228.229; 6.B.228.230;6.B.228.231; 6.B.228.236; 6.B.228.237; 6.B.228.238; 6.B.228.239;6.B.228.154; 6.B.228.157; 6.B.228.166; 6.B.228.169; 6.B.228.172;6.B.228.175; 6.B.228.240; 6.B.228.244; 6.B.229.228; 6.B.229.229;6.B.229.230; 6.B.229.231; 6.B.229.236; 6.B.229.237; 6.B.229.238;6.B.229.239; 6.B.229.154; 6.B.229.157; 6.B.229.166; 6.B.229.169;6.B.229.172; 6.B.229.175; 6.B.229.240; 6.B.229.244; 6.B.230.228;6.B.230.229; 6.B.230.230; 6.B.230.231; 6.B.230.236; 6.B.230.237;6.B.230.238; 6.B.230.239; 6.B.230.154; 6.B.230.157; 6.B.230.166;6.B.230.169; 6.B.230.172; 6.B.230.175; 6.B.230.240; 6.B.230.244;6.B.231.228; 6.B.231.229; 6.B.231.230; 6.B.231.231; 6.B.231.236;6.B.231.237; 6.B.231.238; 6.B.231.239; 6.B.231.154; 6.B.231.157;6.B.231.166; 6.B.231.169; 6.B.231.172; 6.B.231.175; 6.B.231.240;6.B.231.244; 6.B.236.228; 6.B.236.229; 6.B.236.230; 6.B.236.231;6.B.236.236; 6.B.236.237; 6.B.236.238; 6.B.236.239; 6.B.236.154;6.B.236.157; 6.B.236.166; 6.B.236.169; 6.B.236.172; 6.B.236.175;6.B.236.240; 6.B.236.244; 6.B.237.228; 6.B.237.229; 6.B.237.230;6.B.237.231; 6.B.237.236; 6.B.237.237; 6.B.237.238; 6.B.237.239;6.B.237.154; 6.B.237.157; 6.B.237.166; 6.B.237.169; 6.B.237.172;6.B.237.175; 6.B.237.240; 6.B.237.244; 6.B.238.228; 6.B.238.229;6.B.238.230; 6.B.238.231; 6.B.238.236; 6.B.238.237; 6.B.238.238;6.B.238.239; 6.B.238.154; 6.B.238.157; 6.B.238.166; 6.B.238.169;6.B.238.172; 6.B.238.175; 6.B.238.240; 6.B.238.244; 6.B.239.228;6.B.239.229; 6.B.239.230; 6.B.239.231; 6.B.239.236; 6.B.239.237;6.B.239.238; 6.B.239.239; 6.B.239.154; 6.B.239.157; 6.B.239.166;6.B.239.169; 6.B.239.172; 6.B.239.175; 6.B.239.240; 6.B.239.244;6.B.154.228; 6.B.154.229; 6.B.154.230; 6.B.154.231; 6.B.154.236;6.B.154.237; 6.B.154.238; 6.B.154.239; 6.B.154.154; 6.B.154.157;6.B.154.166; 6.B.154.169; 6.B.154.172; 6.B.154.175; 6.B.154.240;6.B.154.244; 6.B.157.228; 6.B.157.229; 6.B.157.230; 6.B.157.231;6.B.157.236; 6.B.157.237; 6.B.157.238; 6.B.157.239; 6.B.157.154;6.B.157.157; 6.B.157.166; 6.B.157.169; 6.B.157.172; 6.B.157.175;6.B.157.240; 6.B.157.244; 6.B.166.228; 6.B.166.229; 6.B.166.230;6.B.166.231; 6.B.166.236; 6.B.166.237; 6.B.166.238; 6.B.166.239;6.B.166.154; 6.B.166.157; 6.B.166.166; 6.B.166.169; 6.B.166.172;6.B.166.175; 6.B.166.240; 6.B.166.244; 6.B.169.228; 6.B.169.229;6.B.169.230; 6.B.169.231; 6.B.169.236; 6.B.169.237; 6.B.169.238;6.B.169.239; 6.B.169.154; 6.B.169.157; 6.B.169.166; 6.B.169.169;6.B.169.172; 6.B.169.175; 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6.D.244.172; 6.D.244.175; 6.D.244.240; 6.D.244.244;Prodrugs of 6.E 6.E.228.228; 6.E.228.229; 6.E.228.230; 6.E.228.231;6.E.228.236; 6.E.228.237; 6.E.228.238; 6.E.228.239; 6.E.228.154;6.E.228.157; 6.E.228.166; 6.E.228.169; 6.E.228.172; 6.E.228.175;6.E.228.240; 6.E.228.244; 6.E.229.228; 6.E.229.229; 6.E.229.230;6.E.229.231; 6.E.229.236; 6.E.229.237; 6.E.229.238; 6.E.229.239;6.E.229.154; 6.E.229.157; 6.E.229.166; 6.E.229.169; 6.E.229.172;6.E.229.175; 6.E.229.240; 6.E.229.244; 6.E.230.228; 6.E.230.229;6.E.230.230; 6.E.230.231; 6.E.230.236; 6.E.230.237; 6.E.230.238;6.E.230.239; 6.E.230.154; 6.E.230.157; 6.E.230.166; 6.E.230.169;6.E.230.172; 6.E.230.175; 6.E.230.240; 6.E.230.244; 6.E.231.228;6.E.231.229; 6.E.231.230; 6.E.231.231; 6.E.231.236; 6.E.231.237;6.E.231.238; 6.E.231.239; 6.E.231.154; 6.E.231.157; 6.E.231.166;6.E.231.169; 6.E.231.172; 6.E.231.175; 6.E.231.240; 6.E.231.244;6.E.236.228; 6.E.236.229; 6.E.236.230; 6.E.236.231; 6.E.236.236;6.E.236.237; 6.E.236.238; 6.E.236.239; 6.E.236.154; 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6.E.240.239; 6.E.240.154; 6.E.240.157;6.E.240.166; 6.E.240.169; 6.E.240.172; 6.E.240.175; 6.E.240.240;6.E.240.244; 6.E.244.228; 6.E.244.229; 6.E.244.230; 6.E.244.231;6.E.244.236; 6.E.244.237; 6.E.244.238; 6.E.244.239; 6.E.244.154;6.E.244.157; 6.E.244.166; 6.E.244.169; 6.E.244.172; 6.E.244.175;6.E.244.240; 6.E.244.244; Prodrugs of 6.G 6.G.228.228; 6.G.228.229;6.G.228.230; 6.G.228.231; 6.G.228.236; 6.G.228.237; 6.G.228.238;6.G.228.239; 6.G.228.154; 6.G.228.157; 6.G.228.166; 6.G.228.169;6.G.228.172; 6.G.228.175; 6.G.228.240; 6.G.228.244; 6.G.229.228;6.G.229.229; 6.G.229.230; 6.G.229.231; 6.G.229.236; 6.G.229.237;6.G.229.238; 6.G.229.239; 6.G.229.154; 6.G.229.157; 6.G.229.166;6.G.229.169; 6.G.229.172; 6.G.229.175; 6.G.229.240; 6.G.229.244;6.G.230.228; 6.G.230.229; 6.G.230.230; 6.G.230.231; 6.G.230.236;6.G.230.237; 6.G.230.238; 6.G.230.239; 6.G.230.154; 6.G.230.157;6.G.230.166; 6.G.230.169; 6.G.230.172; 6.G.230.175; 6.G.230.240;6.G.230.244; 6.G.231.228; 6.G.231.229; 6.G.231.230; 6.G.231.231;6.G.231.236; 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6.G.154.237; 6.G.154.238; 6.G.154.239; 6.G.154.154;6.G.154.157; 6.G.154.166; 6.G.154.169; 6.G.154.172; 6.G.154.175;6.G.154.240; 6.G.154.244; 6.G.157.228; 6.G.157.229; 6.G.157.230;6.G.157.231; 6.G.157.236; 6.G.157.237; 6.G.157.238; 6.G.157.239;6.G.157.154; 6.G.157.157; 6.G.157.166; 6.G.157.169; 6.G.157.172;6.G.157.175; 6.G.157.240; 6.G.157.244; 6.G.166.228; 6.G.166.229;6.G.166.230; 6.G.166.231; 6.G.166.236; 6.G.166.237; 6.G.166.238;6.G.166.239; 6.G.166.154; 6.G.166.157; 6.G.166.166; 6.G.166.169;6.G.166.172; 6.G.166.175; 6.G.166.240; 6.G.166.244; 6.G.169.228;6.G.169.229; 6.G.169.230; 6.G.169.231; 6.G.169.236; 6.G.169.237;6.G.169.238; 6.G.169.239; 6.G.169.154; 6.G.169.157; 6.G.169.166;6.G.169.169; 6.G.169.172; 6.G.169.175; 6.G.169.240; 6.G.169.244;6.G.172.228; 6.G.172.229; 6.G.172.230; 6.G.172.231; 6.G.172.236;6.G.172.237; 6.G.172.238; 6.G.172.239; 6.G.172.154; 6.G.172.157;6.G.172.166; 6.G.172.169; 6.G.172.172; 6.G.172.175; 6.G.172.240;6.G.172.244; 6.G.175.228; 6.G.175.229; 6.G.175.230; 6.G.175.231;6.G.175.236; 6.G.175.237; 6.G.175.238; 6.G.175.239; 6.G.175.154;6.G.175.157; 6.G.175.166; 6.G.175.169; 6.G.175.172; 6.G.175.175;6.G.175.240; 6.G.175.244; 6.G.240.228; 6.G.240.229; 6.G.240.230;6.G.240.231; 6.G.240.236; 6.G.240.237; 6.G.240.238; 6.G.240.239;6.G.240.154; 6.G.240.157; 6.G.240.166; 6.G.240.169; 6.G.240.172;6.G.240.175; 6.G.240.240; 6.G.240.244; 6.G.244.228; 6.G.244.229;6.G.244.230; 6.G.244.231; 6.G.244.236; 6.G.244.237; 6.G.244.238;6.G.244.239; 6.G.244.154; 6.G.244.157; 6.G.244.166; 6.G.244.169;6.G.244.172; 6.G.244.175; 6.G.244.240; 6.G.244.244; Prodrugs of 6.I6.I.228.228; 6.I.228.229; 6.I.228.230; 6.I.228.231; 6.I.228.236;6.I.228.237; 6.I.228.238; 6.I.228.239; 6.I.228.154; 6.I.228.157;6.I.228.166; 6.I.228.169; 6.I.228.172; 6.I.228.175; 6.I.228.240;6.I.228.244; 6.I.229.228; 6.I.229.229; 6.I.229.230; 6.I.229.231;6.I.229.236; 6.I.229.237; 6.I.229.238; 6.I.229.239; 6.I.229.154;6.I.229.157; 6.I.229.166; 6.I.229.169; 6.I.229.172; 6.I.229.175;6.I.229.240; 6.I.229.244; 6.I.230.228; 6.I.230.229; 6.I.230.230;6.I.230.231; 6.I.230.236; 6.I.230.237; 6.I.230.238; 6.I.230.239;6.I.230.154; 6.I.230.157; 6.I.230.166; 6.I.230.169; 6.I.230.172;6.I.230.175; 6.I.230.240; 6.I.230.244; 6.I.231.228; 6.I.231.229;6.I.231.230; 6.I.231.231; 6.I.231.236; 6.I.231.237; 6.I.231.238;6.I.231.239; 6.I.231.154; 6.I.231.157; 6.I.231.166; 6.I.231.169;6.I.231.172; 6.I.231.175; 6.I.231.240; 6.I.231.244; 6.I.236.228;6.I.236.229; 6.I.236.230; 6.I.236.231; 6.I.236.236; 6.I.236.237;6.I.236.238; 6.I.236.239; 6.I.236.154; 6.I.236.157; 6.I.236.166;6.I.236.169; 6.I.236.172; 6.I.236.175; 6.I.236.240; 6.I.236.244;6.I.237.228; 6.I.237.229; 6.I.237.230; 6.I.237.231; 6.I.237.236;6.I.237.237; 6.I.237.238; 6.I.237.239; 6.I.237.154; 6.I.237.157;6.I.237.166; 6.I.237.169; 6.I.237.172; 6.I.237.175; 6.I.237.240;6.I.237.244; 6.I.238.228; 6.I.238.229; 6.I.238.230; 6.I.238.231;6.I.238.236; 6.I.238.237; 6.I.238.238; 6.I.238.239; 6.I.238.154;6.I.238.157; 6.I.238.166; 6.I.238.169; 6.I.238.172; 6.I.238.175;6.I.238.240; 6.I.238.244; 6.I.239.228; 6.I.239.229; 6.I.239.230;6.I.239.231; 6.I.239.236; 6.I.239.237; 6.I.239.238; 6.I.239.239;6.I.239.154; 6.I.239.157; 6.I.239.166; 6.I.239.169; 6.I.239.172;6.I.239.175; 6.I.239.240; 6.I.239.244; 6.I.154.228; 6.I.154.229;6.I.154.230; 6.I.154.231; 6.I.154.236; 6.I.154.237; 6.I.154.238;6.I.154.239; 6.I.154.154; 6.I.154.157; 6.I.154.166; 6.I.154.169;6.I.154.172; 6.I.154.175; 6.I.154.240; 6.I.154.244; 6.I.157.228;6.I.157.229; 6.I.157.230; 6.I.157.231; 6.I.157.236; 6.I.157.237;6.I.157.238; 6.I.157.239; 6.I.157.154; 6.I.157.157; 6.I.157.166;6.I.157.169; 6.I.157.172; 6.I.157.175; 6.I.157.240; 6.I.157.244;6.I.166.228; 6.I.166.229; 6.I.166.230; 6.I.166.231; 6.I.166.236;6.I.166.237; 6.I.166.238; 6.I.166.239; 6.I.166.154; 6.I.166.157;6.I.166.166; 6.I.166.169; 6.I.166.172; 6.I.166.175; 6.I.166.240;6.I.166.244; 6.I.169.228; 6.I.169.229; 6.I.169.230; 6.I.169.231;6.I.169.236; 6.I.169.237; 6.I.169.238; 6.I.169.239; 6.I.169.154;6.I.169.157; 6.I.169.166; 6.I.169.169; 6.I.169.172; 6.I.169.175;6.I.169.240; 6.I.169.244; 6.I.172.228; 6.I.172.229; 6.I.172.230;6.I.172.231; 6.I.172.236; 6.I.172.237; 6.I.172.238; 6.I.172.239;6.I.172.154; 6.I.172.157; 6.I.172.166; 6.I.172.169; 6.I.172.172;6.I.172.175; 6.I.172.240; 6.I.172.244; 6.I.175.228; 6.I.175.229;6.I.175.230; 6.I.175.231; 6.I.175.236; 6.I.175.237; 6.I.175.238;6.I.175.239; 6.I.175.154; 6.I.175.157; 6.I.175.166; 6.I.175.169;6.I.175.172; 6.I.175.175; 6.I.175.240; 6.I.175.244; 6.I.240.228;6.I.240.229; 6.I.240.230; 6.I.240.231; 6.I.240.236; 6.I.240.237;6.I.240.238; 6.I.240.239; 6.I.240.154; 6.I.240.157; 6.I.240.166;6.I.240.169; 6.I.240.172; 6.I.240.175; 6.I.240.240; 6.I.240.244;6.I.244.228; 6.I.244.229; 6.I.244.230; 6.I.244.231; 6.I.244.236;6.I.244.237; 6.I.244.238; 6.I.244.239; 6.I.244.154; 6.I.244.157;6.I.244.166; 6.I.244.169; 6.I.244.172; 6.I.244.175; 6.I.244.240;6.I.244.244; Prodrugs of 6.J 6.J.228.228; 6.J.228.229; 6.J.228.230;6.J.228.231; 6.J.228.236; 6.J.228.237; 6.J.228.238; 6.J.228.239;6.J.228.154; 6.J.228.157; 6.J.228.166; 6.J.228.169; 6.J.228.172;6.J.228.175; 6.J.228.240; 6.J.228.244; 6.J.229.228; 6.J.229.229;6.J.229.230; 6.J.229.231; 6.J.229.236; 6.J.229.237; 6.J.229.238;6.J.229.239; 6.J.229.154; 6.J.229.157; 6.J.229.166; 6.J.229.169;6.J.229.172; 6.J.229.175; 6.J.229.240; 6.J.229.244; 6.J.230.228;6.J.230.229; 6.J.230.230; 6.J.230.231; 6.J.230.236; 6.J.230.237;6.J.230.238; 6.J.230.239; 6.J.230.154; 6.J.230.157; 6.J.230.166;6.J.230.169; 6.J.230.172; 6.J.230.175; 6.J.230.240; 6.J.230.244;6.J.231.228; 6.J.231.229; 6.J.231.230; 6.J.231.231; 6.J.231.236;6.J.231.237; 6.J.231.238; 6.J.231.239; 6.J.231.154; 6.J.231.157;6.J.231.166; 6.J.231.169; 6.J.231.172; 6.J.231.175; 6.J.231.240;6.J.231.244; 6.J.236.228; 6.J.236.229; 6.J.236.230; 6.J.236.231;6.J.236.236; 6.J.236.237; 6.J.236.238; 6.J.236.239; 6.J.236.154;6.J.236.157; 6.J.236.166; 6.J.236.169; 6.J.236.172; 6.J.236.175;6.J.236.240; 6.J.236.244; 6.J.237.228; 6.J.237.229; 6.J.237.230;6.J.237.231; 6.J.237.236; 6.J.237.237; 6.J.237.238; 6.J.237.239;6.J.237.154; 6.J.237.157; 6.J.237.166; 6.J.237.169; 6.J.237.172;6.J.237.175; 6.J.237.240; 6.J.237.244; 6.J.238.228; 6.J.238.229;6.J.238.230; 6.J.238.231; 6.J.238.236; 6.J.238.237; 6.J.238.238;6.J.238.239; 6.J.238.154; 6.J.238.157; 6.J.238.166; 6.J.238.169;6.J.238.172; 6.J.238.175; 6.J.238.240; 6.J.238.244; 6.J.239.228;6.J.239.229; 6.J.239.230; 6.J.239.231; 6.J.239.236; 6.J.239.237;6.J.239.238; 6.J.239.239; 6.J.239.154; 6.J.239.157; 6.J.239.166;6.J.239.169; 6.J.239.172; 6.J.239.175; 6.J.239.240; 6.J.239.244;6.J.154.228; 6.J.154.229; 6.J.154.230; 6.J.154.231; 6.J.154.236;6.J.154.237; 6.J.154.238; 6.J.154.239; 6.J.154.154; 6.J.154.157;6.J.154.166; 6.J.154.169; 6.J.154.172; 6.J.154.175; 6.J.154.240;6.J.154.244; 6.J.157.228; 6.J.157.229; 6.J.157.230; 6.J.157.231;6.J.157.236; 6.J.157.237; 6.J.157.238; 6.J.157.239; 6.J.157.154;6.J.157.157; 6.J.157.166; 6.J.157.169; 6.J.157.172; 6.J.157.175;6.J.157.240; 6.J.157.244; 6.J.166.228; 6.J.166.229; 6.J.166.230;6.J.166.231; 6.J.166.236; 6.J.166.237; 6.J.166.238; 6.J.166.239;6.J.166.154; 6.J.166.157; 6.J.166.166; 6.J.166.169; 6.J.166.172;6.J.166.175; 6.J.166.240; 6.J.166.244; 6.J.169.228; 6.J.169.229;6.J.169.230; 6.J.169.231; 6.J.169.236; 6.J.169.237; 6.J.169.238;6.J.169.239; 6.J.169.154; 6.J.169.157; 6.J.169.166; 6.J.169.169;6.J.169.172; 6.J.169.175; 6.J.169.240; 6.J.169.244; 6.J.172.228;6.J.172.229; 6.J.172.230; 6.J.172.231; 6.J.172.236; 6.J.172.237;6.J.172.238; 6.J.172.239; 6.J.172.154; 6.J.172.157; 6.J.172.166;6.J.172.169; 6.J.172.172; 6.J.172.175; 6.J.172.240; 6.J.172.244;6.J.175.228; 6.J.175.229; 6.J.175.230; 6.J.175.231; 6.J.175.236;6.J.175.237; 6.J.175.238; 6.J.175.239; 6.J.175.154; 6.J.175.157;6.J.175.166; 6.J.175.169; 6.J.175.172; 6.J.175.175; 6.J.175.240;6.J.175.244; 6.J.240.228; 6.J.240.229; 6.J.240.230; 6.J.240.231;6.J.240.236; 6.J.240.237; 6.J.240.238; 6.J.240.239; 6.J.240.154;6.J.240.157; 6.J.240.166; 6.J.240.169; 6.J.240.172; 6.J.240.175;6.J.240.240; 6.J.240.244; 6.J.244.228; 6.J.244.229; 6.J.244.230;6.J.244.231; 6.J.244.236; 6.J.244.237; 6.J.244.238; 6.J.244.239;6.J.244.154; 6.J.244.157; 6.J.244.166; 6.J.244.169; 6.J.244.172;6.J.244.175; 6.J.244.240; 6.J.244.244; Prodrugs of 6.L 6.L.228.228;6.L.228.229; 6.L.228.230; 6.L.228.231; 6.L.228.236; 6.L.228.237;6.L.228.238; 6.L.228.239; 6.L.228.154; 6.L.228.157; 6.L.228.166;6.L.228.169; 6.L.228.172; 6.L.228.175; 6.L.228.240; 6.L.228.244;6.L.229.228; 6.L.229.229; 6.L.229.230; 6.L.229.231; 6.L.229.236;6.L.229.237; 6.L.229.238; 6.L.229.239; 6.L.229.154; 6.L.229.157;6.L.229.166; 6.L.229.169; 6.L.229.172; 6.L.229.175; 6.L.229.240;6.L.229.244; 6.L.230.228; 6.L.230.229; 6.L.230.230; 6.L.230.231;6.L.230.236; 6.L.230.237; 6.L.230.238; 6.L.230.239; 6.L.230.154;6.L.230.157; 6.L.230.166; 6.L.230.169; 6.L.230.172; 6.L.230.175;6.L.230.240; 6.L.230.244; 6.L.231.228; 6.L.231.229; 6.L.231.230;6.L.231.231; 6.L.231.236; 6.L.231.237; 6.L.231.238; 6.L.231.239;6.L.231.154; 6.L.231.157; 6.L.231.166; 6.L.231.169; 6.L.231.172;6.L.231.175; 6.L.231.240; 6.L.231.244; 6.L.236.228; 6.L.236.229;6.L.236.230; 6.L.236.231; 6.L.236.236; 6.L.236.237; 6.L.236.238;6.L.236.239; 6.L.236.154; 6.L.236.157; 6.L.236.166; 6.L.236.169;6.L.236.172; 6.L.236.175; 6.L.236.240; 6.L.236.244; 6.L.237.228;6.L.237.229; 6.L.237.230; 6.L.237.231; 6.L.237.236; 6.L.237.237;6.L.237.238; 6.L.237.239; 6.L.237.154; 6.L.237.157; 6.L.237.166;6.L.237.169; 6.L.237.172; 6.L.237.175; 6.L.237.240; 6.L.237.244;6.L.238.228; 6.L.238.229; 6.L.238.230; 6.L.238.231; 6.L.238.236;6.L.238.237; 6.L.238.238; 6.L.238.239; 6.L.238.154; 6.L.238.157;6.L.238.166; 6.L.238.169; 6.L.238.172; 6.L.238.175; 6.L.238.240;6.L.238.244; 6.L.239.228; 6.L.239.229; 6.L.239.230; 6.L.239.231;6.L.239.236; 6.L.239.237; 6.L.239.238; 6.L.239.239; 6.L.239.154;6.L.239.157; 6.L.239.166; 6.L.239.169; 6.L.239.172; 6.L.239.175;6.L.239.240; 6.L.239.244; 6.L.154.228; 6.L.154.229; 6.L.154.230;6.L.154.231; 6.L.154.236; 6.L.154.237; 6.L.154.238; 6.L.154.239;6.L.154.154; 6.L.154.157; 6.L.154.166; 6.L.154.169; 6.L.154.172;6.L.154.175; 6.L.154.240; 6.L.154.244; 6.L.157.228; 6.L.157.229;6.L.157.230; 6.L.157.231; 6.L.157.236; 6.L.157.237; 6.L.157.238;6.L.157.239; 6.L.157.154; 6.L.157.157; 6.L.157.166; 6.L.157.169;6.L.157.172; 6.L.157.175; 6.L.157.240; 6.L.157.244; 6.L.166.228;6.L.166.229; 6.L.166.230; 6.L.166.231; 6.L.166.236; 6.L.166.237;6.L.166.238; 6.L.166.239; 6.L.166.154; 6.L.166.157; 6.L.166.166;6.L.166.169; 6.L.166.172; 6.L.166.175; 6.L.166.240; 6.L.166.244;6.L.169.228; 6.L.169.229; 6.L.169.230; 6.L.169.231; 6.L.169.236;6.L.169.237; 6.L.169.238; 6.L.169.239; 6.L.169.154; 6.L.169.157;6.L.169.166; 6.L.169.169; 6.L.169.172; 6.L.169.175; 6.L.169.240;6.L.169.244; 6.L.172.228; 6.L.172.229; 6.L.172.230; 6.L.172.231;6.L.172.236; 6.L.172.237; 6.L.172.238; 6.L.172.239; 6.L.172.154;6.L.172.157; 6.L.172.166; 6.L.172.169; 6.L.172.172; 6.L.172.175;6.L.172.240; 6.L.172.244; 6.L.175.228; 6.L.175.229; 6.L.175.230;6.L.175.231; 6.L.175.236; 6.L.175.237; 6.L.175.238; 6.L.175.239;6.L.175.154; 6.L.175.157; 6.L.175.166; 6.L.175.169; 6.L.175.172;6.L.175.175; 6.L.175.240; 6.L.175.244; 6.L.240.228; 6.L.240.229;6.L.240.230; 6.L.240.231; 6.L.240.236; 6.L.240.237; 6.L.240.238;6.L.240.239; 6.L.240.154; 6.L.240.157; 6.L.240.166; 6.L.240.169;6.L.240.172; 6.L.240.175; 6.L.240.240; 6.L.240.244; 6.L.244.228;6.L.244.229; 6.L.244.230; 6.L.244.231; 6.L.244.236; 6.L.244.237;6.L.244.238; 6.L.244.239; 6.L.244.154; 6.L.244.157; 6.L.244.166;6.L.244.169; 6.L.244.172; 6.L.244.175; 6.L.244.240; 6.L.244.244;Prodrugs of 6.O 6.O.228.228; 6.O.228.229; 6.O.228.230; 6.O.228.231;6.O.228.236; 6.O.228.237; 6.O.228.238; 6.O.228.239; 6.O.228.154;6.O.228.157; 6.O.228.166; 6.O.228.169; 6.O.228.172; 6.O.228.175;6.O.228.240; 6.O.228.244; 6.O.229.228; 6.O.229.229; 6.O.229.230;6.O.229.231; 6.O.229.236; 6.O.229.237; 6.O.229.238; 6.O.229.239;6.O.229.154; 6.O.229.157; 6.O.229.166; 6.O.229.169; 6.O.229.172;6.O.229.175; 6.O.229.240; 6.O.229.244; 6.O.230.228; 6.O.230.229;6.O.230.230; 6.O.230.231; 6.O.230.236; 6.O.230.237; 6.O.230.238;6.O.230.239; 6.O.230.154; 6.O.230.157; 6.O.230.166; 6.O.230.169;6.O.230.172; 6.O.230.175; 6.O.230.240; 6.O.230.244; 6.O.231.228;6.O.231.229; 6.O.231.230; 6.O.231.231; 6.O.231.236; 6.O.231.237;6.O.231.238; 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6.O.154.239; 6.O.154.154; 6.O.154.157; 6.O.154.166;6.O.154.169; 6.O.154.172; 6.O.154.175; 6.O.154.240; 6.O.154.244;6.O.157.228; 6.O.157.229; 6.O.157.230; 6.O.157.231; 6.O.157.236;6.O.157.237; 6.O.157.238; 6.O.157.239; 6.O.157.154; 6.O.157.157;6.O.157.166; 6.O.157.169; 6.O.157.172; 6.O.157.175; 6.O.157.240;6.O.157.244; 6.O.166.228; 6.O.166.229; 6.O.166.230; 6.O.166.231;6.O.166.236; 6.O.166.237; 6.O.166.238; 6.O.166.239; 6.O.166.154;6.O.166.157; 6.O.166.166; 6.O.166.169; 6.O.166.172; 6.O.166.175;6.O.166.240; 6.O.166.244; 6.O.169.228; 6.O.169.229; 6.O.169.230;6.O.169.231; 6.O.169.236; 6.O.169.237; 6.O.169.238; 6.O.169.239;6.O.169.154; 6.O.169.157; 6.O.169.166; 6.O.169.169; 6.O.169.172;6.O.169.175; 6.O.169.240; 6.O.169.244; 6.O.172.228; 6.O.172.229;6.O.172.230; 6.O.172.231; 6.O.172.236; 6.O.172.237; 6.O.172.238;6.O.172.239; 6.O.172.154; 6.O.172.157; 6.O.172.166; 6.O.172.169;6.O.172.172; 6.O.172.175; 6.O.172.240; 6.O.172.244; 6.O.175.228;6.O.175.229; 6.O.175.230; 6.O.175.231; 6.O.175.236; 6.O.175.237;6.O.175.238; 6.O.175.239; 6.O.175.154; 6.O.175.157; 6.O.175.166;6.O.175.169; 6.O.175.172; 6.O.175.175; 6.O.175.240; 6.O.175.244;6.O.240.228; 6.O.240.229; 6.O.240.230; 6.O.240.231; 6.O.240.236;6.O.240.237; 6.O.240.238; 6.O.240.239; 6.O.240.154; 6.O.240.157;6.O.240.166; 6.O.240.169; 6.O.240.172; 6.O.240.175; 6.O.240.240;6.O.240.244; 6.O.244.228; 6.O.244.229; 6.O.244.230; 6.O.244.231;6.O.244.236; 6.O.244.237; 6.O.244.238; 6.O.244.239; 6.O.244.154;6.O.244.157; 6.O.244.166; 6.O.244.169; 6.O.244.172; 6.O.244.175;6.O.244.240; 6.O.244.244; Prodrugs of 6.P 6.P.228.228; 6.P.228.229;6.P.228.230; 6.P.228.231; 6.P.228.236; 6.P.228.237; 6.P.228.238;6.P.228.239; 6.P.228.154; 6.P.228.157; 6.P.228.166; 6.P.228.169;6.P.228.172; 6.P.228.175; 6.P.228.240; 6.P.228.244; 6.P.229.228;6.P.229.229; 6.P.229.230; 6.P.229.231; 6.P.229.236; 6.P.229.237;6.P.229.238; 6.P.229.239; 6.P.229.154; 6.P.229.157; 6.P.229.166;6.P.229.169; 6.P.229.172; 6.P.229.175; 6.P.229.240; 6.P.229.244;6.P.230.228; 6.P.230.229; 6.P.230.230; 6.P.230.231; 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6.P.172.230; 6.P.172.231; 6.P.172.236;6.P.172.237; 6.P.172.238; 6.P.172.239; 6.P.172.154; 6.P.172.157;6.P.172.166; 6.P.172.169; 6.P.172.172; 6.P.172.175; 6.P.172.240;6.P.172.244; 6.P.175.228; 6.P.175.229; 6.P.175.230; 6.P.175.231;6.P.175.236; 6.P.175.237; 6.P.175.238; 6.P.175.239; 6.P.175.154;6.P.175.157; 6.P.175.166; 6.P.175.169; 6.P.175.172; 6.P.175.175;6.P.175.240; 6.P.175.244; 6.P.240.228; 6.P.240.229; 6.P.240.230;6.P.240.231; 6.P.240.236; 6.P.240.237; 6.P.240.238; 6.P.240.239;6.P.240.154; 6.P.240.157; 6.P.240.166; 6.P.240.169; 6.P.240.172;6.P.240.175; 6.P.240.240; 6.P.240.244; 6.P.244.228; 6.P.244.229;6.P.244.230; 6.P.244.231; 6.P.244.236; 6.P.244.237; 6.P.244.238;6.P.244.239; 6.P.244.154; 6.P.244.157; 6.P.244.166; 6.P.244.169;6.P.244.172; 6.P.244.175; 6.P.244.240; 6.P.244.244; Prodrugs of 6.U6.U.228.228; 6.U.228.229; 6.U.228.230; 6.U.228.231; 6.U.228.236;6.U.228.237; 6.U.228.238; 6.U.228.239; 6.U.228.154; 6.U.228.157;6.U.228.166; 6.U.228.169; 6.U.228.172; 6.U.228.175; 6.U.228.240;6.U.228.244; 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6.U.238.228; 6.U.238.229; 6.U.238.230; 6.U.238.231;6.U.238.236; 6.U.238.237; 6.U.238.238; 6.U.238.239; 6.U.238.154;6.U.238.157; 6.U.238.166; 6.U.238.169; 6.U.238.172; 6.U.238.175;6.U.238.240; 6.U.238.244; 6.U.239.228; 6.U.239.229; 6.U.239.230;6.U.239.231; 6.U.239.236; 6.U.239.237; 6.U.239.238; 6.U.239.239;6.U.239.154; 6.U.239.157; 6.U.239.166; 6.U.239.169; 6.U.239.172;6.U.239.175; 6.U.239.240; 6.U.239.244; 6.U.154.228; 6.U.154.229;6.U.154.230; 6.U.154.231; 6.U.154.236; 6.U.154.237; 6.U.154.238;6.U.154.239; 6.U.154.154; 6.U.154.157; 6.U.154.166; 6.U.154.169;6.U.154.172; 6.U.154.175; 6.U.154.240; 6.U.154.244; 6.U.157.228;6.U.157.229; 6.U.157.230; 6.U.157.231; 6.U.157.236; 6.U.157.237;6.U.157.238; 6.U.157.239; 6.U.157.154; 6.U.157.157; 6.U.157.166;6.U.157.169; 6.U.157.172; 6.U.157.175; 6.U.157.240; 6.U.157.244;6.U.166.228; 6.U.166.229; 6.U.166.230; 6.U.166.231; 6.U.166.236;6.U.166.237; 6.U.166.238; 6.U.166.239; 6.U.166.154; 6.U.166.157;6.U.166.166; 6.U.166.169; 6.U.166.172; 6.U.166.175; 6.U.166.240;6.U.166.244; 6.U.169.228; 6.U.169.229; 6.U.169.230; 6.U.169.231;6.U.169.236; 6.U.169.237; 6.U.169.238; 6.U.169.239; 6.U.169.154;6.U.169.157; 6.U.169.166; 6.U.169.169; 6.U.169.172; 6.U.169.175;6.U.169.240; 6.U.169.244; 6.U.172.228; 6.U.172.229; 6.U.172.230;6.U.172.231; 6.U.172.236; 6.U.172.237; 6.U.172.238; 6.U.172.239;6.U.172.154; 6.U.172.157; 6.U.172.166; 6.U.172.169; 6.U.172.172;6.U.172.175; 6.U.172.240; 6.U.172.244; 6.U.175.228; 6.U.175.229;6.U.175.230; 6.U.175.231; 6.U.175.236; 6.U.175.237; 6.U.175.238;6.U.175.239; 6.U.175.154; 6.U.175.157; 6.U.175.166; 6.U.175.169;6.U.175.172; 6.U.175.175; 6.U.175.240; 6.U.175.244; 6.U.240.228;6.U.240.229; 6.U.240.230; 6.U.240.231; 6.U.240.236; 6.U.240.237;6.U.240.238; 6.U.240.239; 6.U.240.154; 6.U.240.157; 6.U.240.166;6.U.240.169; 6.U.240.172; 6.U.240.175; 6.U.240.240; 6.U.240.244;6.U.244.228; 6.U.244.229; 6.U.244.230; 6.U.244.231; 6.U.244.236;6.U.244.237; 6.U.244.238; 6.U.244.239; 6.U.244.154; 6.U.244.157;6.U.244.166; 6.U.244.169; 6.U.244.172; 6.U.244.175; 6.U.244.240;6.U.244.244; Prodrugs of 6.W 6.W.228.228; 6.W.228.229; 6.W.228.230;6.W.228.231; 6.W.228.236; 6.W.228.237; 6.W.228.238; 6.W.228.239;6.W.228.154; 6.W.228.157; 6.W.228.166; 6.W.228.169; 6.W.228.172;6.W.228.175; 6.W.228.240; 6.W.228.244; 6.W.229.228; 6.W.229.229;6.W.229.230; 6.W.229.231; 6.W.229.236; 6.W.229.237; 6.W.229.238;6.W.229.239; 6.W.229.154; 6.W.229.157; 6.W.229.166; 6.W.229.169;6.W.229.172; 6.W.229.175; 6.W.229.240; 6.W.229.244; 6.W.230.228;6.W.230.229; 6.W.230.230; 6.W.230.231; 6.W.230.236; 6.W.230.237;6.W.230.238; 6.W.230.239; 6.W.230.154; 6.W.230.157; 6.W.230.166;6.W.230.169; 6.W.230.172; 6.W.230.175; 6.W.230.240; 6.W.230.244;6.W.231.228; 6.W.231.229; 6.W.231.230; 6.W.231.231; 6.W.231.236;6.W.231.237; 6.W.231.238; 6.W.231.239; 6.W.231.154; 6.W.231.157;6.W.231.166; 6.W.231.169; 6.W.231.172; 6.W.231.175; 6.W.231.240;6.W.231.244; 6.W.236.228; 6.W.236.229; 6.W.236.230; 6.W.236.231;6.W.236.236; 6.W.236.237; 6.W.236.238; 6.W.236.239; 6.W.236.154;6.W.236.157; 6.W.236.166; 6.W.236.169; 6.W.236.172; 6.W.236.175;6.W.236.240; 6.W.236.244; 6.W.237.228; 6.W.237.229; 6.W.237.230;6.W.237.231; 6.W.237.236; 6.W.237.237; 6.W.237.238; 6.W.237.239;6.W.237.154; 6.W.237.157; 6.W.237.166; 6.W.237.169; 6.W.237.172;6.W.237.175; 6.W.237.240; 6.W.237.244; 6.W.238.228; 6.W.238.229;6.W.238.230; 6.W.238.231; 6.W.238.236; 6.W.238.237; 6.W.238.238;6.W.238.239; 6.W.238.154; 6.W.238.157; 6.W.238.166; 6.W.238.169;6.W.238.172; 6.W.238.175; 6.W.238.240; 6.W.238.244; 6.W.239.228;6.W.239.229; 6.W.239.230; 6.W.239.231; 6.W.239.236; 6.W.239.237;6.W.239.238; 6.W.239.239; 6.W.239.154; 6.W.239.157; 6.W.239.166;6.W.239.169; 6.W.239.172; 6.W.239.175; 6.W.239.240; 6.W.239.244;6.W.154.228; 6.W.154.229; 6.W.154.230; 6.W.154.231; 6.W.154.236;6.W.154.237; 6.W.154.238; 6.W.154.239; 6.W.154.154; 6.W.154.157;6.W.154.166; 6.W.154.169; 6.W.154.172; 6.W.154.175; 6.W.154.240;6.W.154.244; 6.W.157.228; 6.W.157.229; 6.W.157.230; 6.W.157.231;6.W.157.236; 6.W.157.237; 6.W.157.238; 6.W.157.239; 6.W.157.154;6.W.157.157; 6.W.157.166; 6.W.157.169; 6.W.157.172; 6.W.157.175;6.W.157.240; 6.W.157.244; 6.W.166.228; 6.W.166.229; 6.W.166.230;6.W.166.231; 6.W.166.236; 6.W.166.237; 6.W.166.238; 6.W.166.239;6.W.166.154; 6.W.166.157; 6.W.166.166; 6.W.166.169; 6.W.166.172;6.W.166.175; 6.W.166.240; 6.W.166.244; 6.W.169.228; 6.W.169.229;6.W.169.230; 6.W.169.231; 6.W.169.236; 6.W.169.237; 6.W.169.238;6.W.169.239; 6.W.169.154; 6.W.169.157; 6.W.169.166; 6.W.169.169;6.W.169.172; 6.W.169.175; 6.W.169.240; 6.W.169.244; 6.W.172.228;6.W.172.229; 6.W.172.230; 6.W.172.231; 6.W.172.236; 6.W.172.237;6.W.172.238; 6.W.172.239; 6.W.172.154; 6.W.172.157; 6.W.172.166;6.W.172.169; 6.W.172.172; 6.W.172.175; 6.W.172.240; 6.W.172.244;6.W.175.228; 6.W.175.229; 6.W.175.230; 6.W.175.231; 6.W.175.236;6.W.175.237; 6.W.175.238; 6.W.175.239; 6.W.175.154; 6.W.175.157;6.W.175.166; 6.W.175.169; 6.W.175.172; 6.W.175.175; 6.W.175.240;6.W.175.244; 6.W.240.228; 6.W.240.229; 6.W.240.230; 6.W.240.231;6.W.240.236; 6.W.240.237; 6.W.240.238; 6.W.240.239; 6.W.240.154;6.W.240.157; 6.W.240.166; 6.W.240.169; 6.W.240.172; 6.W.240.175;6.W.240.240; 6.W.240.244; 6.W.244.228; 6.W.244.229; 6.W.244.230;6.W.244.231; 6.W.244.236; 6.W.244.237; 6.W.244.238; 6.W.244.239;6.W.244.154; 6.W.244.157; 6.W.244.166; 6.W.244.169; 6.W.244.172;6.W.244.175; 6.W.244.240; 6.W.244.244; Prodrugs of 6.Y 6.Y.228.228;6.Y.228.229; 6.Y.228.230; 6.Y.228.231; 6.Y.228.236; 6.Y.228.237;6.Y.228.238; 6.Y.228.239; 6.Y.228.154; 6.Y.228.157; 6.Y.228.166;6.Y.228.169; 6.Y.228.172; 6.Y.228.175; 6.Y.228.240; 6.Y.228.244;6.Y.229.228; 6.Y.229.229; 6.Y.229.230; 6.Y.229.231; 6.Y.229.236;6.Y.229.237; 6.Y.229.238; 6.Y.229.239; 6.Y.229.154; 6.Y.229.157;6.Y.229.166; 6.Y.229.169; 6.Y.229.172; 6.Y.229.175; 6.Y.229.240;6.Y.229.244; 6.Y.230.228; 6.Y.230.229; 6.Y.230.230; 6.Y.230.231;6.Y.230.236; 6.Y.230.237; 6.Y.230.238; 6.Y.230.239; 6.Y.230.154;6.Y.230.157; 6.Y.230.166; 6.Y.230.169; 6.Y.230.172; 6.Y.230.175;6.Y.230.240; 6.Y.230.244; 6.Y.231.228; 6.Y.231.229; 6.Y.231.230;6.Y.231.231; 6.Y.231.236; 6.Y.231.237; 6.Y.231.238; 6.Y.231.239;6.Y.231.154; 6.Y.231.157; 6.Y.231.166; 6.Y.231.169; 6.Y.231.172;6.Y.231.175; 6.Y.231.240; 6.Y.231.244; 6.Y.236.228; 6.Y.236.229;6.Y.236.230; 6.Y.236.231; 6.Y.236.236; 6.Y.236.237; 6.Y.236.238;6.Y.236.239; 6.Y.236.154; 6.Y.236.157; 6.Y.236.166; 6.Y.236.169;6.Y.236.172; 6.Y.236.175; 6.Y.236.240; 6.Y.236.244; 6.Y.237.228;6.Y.237.229; 6.Y.237.230; 6.Y.237.231; 6.Y.237.236; 6.Y.237.237;6.Y.237.238; 6.Y.237.239; 6.Y.237.154; 6.Y.237.157; 6.Y.237.166;6.Y.237.169; 6.Y.237.172; 6.Y.237.175; 6.Y.237.240; 6.Y.237.244;6.Y.238.228; 6.Y.238.229; 6.Y.238.230; 6.Y.238.231; 6.Y.238.236;6.Y.238.237; 6.Y.238.238; 6.Y.238.239; 6.Y.238.154; 6.Y.238.157;6.Y.238.166; 6.Y.238.169; 6.Y.238.172; 6.Y.238.175; 6.Y.238.240;6.Y.238.244; 6.Y.239.228; 6.Y.239.229; 6.Y.239.230; 6.Y.239.231;6.Y.239.236; 6.Y.239.237; 6.Y.239.238; 6.Y.239.239; 6.Y.239.154;6.Y.239.157; 6.Y.239.166; 6.Y.239.169; 6.Y.239.172; 6.Y.239.175;6.Y.239.240; 6.Y.239.244; 6.Y.154.228; 6.Y.154.229; 6.Y.154.230;6.Y.154.231; 6.Y.154.236; 6.Y.154.237; 6.Y.154.238; 6.Y.154.239;6.Y.154.154; 6.Y.154.157; 6.Y.154.166; 6.Y.154.169; 6.Y.154.172;6.Y.154.175; 6.Y.154.240; 6.Y.154.244; 6.Y.157.228; 6.Y.157.229;6.Y.157.230; 6.Y.157.231; 6.Y.157.236; 6.Y.157.237; 6.Y.157.238;6.Y.157.239; 6.Y.157.154; 6.Y.157.157; 6.Y.157.166; 6.Y.157.169;6.Y.157.172; 6.Y.157.175; 6.Y.157.240; 6.Y.157.244; 6.Y.166.228;6.Y.166.229; 6.Y.166.230; 6.Y.166.231; 6.Y.166.236; 6.Y.166.237;6.Y.166.238; 6.Y.166.239; 6.Y.166.154; 6.Y.166.157; 6.Y.166.166;6.Y.166.169; 6.Y.166.172; 6.Y.166.175; 6.Y.166.240; 6.Y.166.244;6.Y.169.228; 6.Y.169.229; 6.Y.169.230; 6.Y.169.231; 6.Y.169.236;6.Y.169.237; 6.Y.169.238; 6.Y.169.239; 6.Y.169.154; 6.Y.169.157;6.Y.169.166; 6.Y.169.169; 6.Y.169.172; 6.Y.169.175; 6.Y.169.240;6.Y.169.244; 6.Y.172.228; 6.Y.172.229; 6.Y.172.230; 6.Y.172.231;6.Y.172.236; 6.Y.172.237; 6.Y.172.238; 6.Y.172.239; 6.Y.172.154;6.Y.172.157; 6.Y.172.166; 6.Y.172.169; 6.Y.172.172; 6.Y.172.175;6.Y.172.240; 6.Y.172.244; 6.Y.175.228; 6.Y.175.229; 6.Y.175.230;6.Y.175.231; 6.Y.175.236; 6.Y.175.237; 6.Y.175.238; 6.Y.175.239;6.Y.175.154; 6.Y.175.157; 6.Y.175.166; 6.Y.175.169; 6.Y.175.172;6.Y.175.175; 6.Y.175.240; 6.Y.175.244; 6.Y.240.228; 6.Y.240.229;6.Y.240.230; 6.Y.240.231; 6.Y.240.236; 6.Y.240.237; 6.Y.240.238;6.Y.240.239; 6.Y.240.154; 6.Y.240.157; 6.Y.240.166; 6.Y.240.169;6.Y.240.172; 6.Y.240.175; 6.Y.240.240; 6.Y.240.244; 6.Y.244.228;6.Y.244.229; 6.Y.244.230; 6.Y.244.231; 6.Y.244.236; 6.Y.244.237;6.Y.244.238; 6.Y.244.239; 6.Y.244.154; 6.Y.244.157; 6.Y.244.166;6.Y.244.169; 6.Y.244.172; 6.Y.244.175; 6.Y.244.240; 6.Y.244.244;Prodrugs of 7.AH 7.AH.4.157; 7.AH.4.158; 7.AH.4.196; 7.AH.4.223;7.AH.4.240; 7.AH.4.244; 7.AH.4.243; 7.AH.4.247; 7.AH.5.157; 7.AH.5.158;7.AH.5.196; 7.AH.5.223; 7.AH.5.240; 7.AH.5.244; 7.AH.5.243; 7.AH.5.247;7.AH.7.157; 7.AH.7.158; 7.AH.7.196; 7.AH.7.223; 7.AH.7.240; 7.AH.7.244;7.AH.7.243; 7.AH.7.247; 7.AH.15.157; 7.AH.15.158; 7.AH.15.196;7.AH.15.223; 7.AH.15.240; 7.AH.15.244; 7.AH.15.243; 7.AH.15.247;7.AH.16.157; 7.AH.16.158; 7.AH.16.196; 7.AH.16.223; 7.AH.16.240;7.AH.16.244; 7.AH.16.243; 7.AH.16.247; 7.AH.18.157; 7.AH.18.158;7.AH.18.196; 7.AH.18.223; 7.AH.18.240; 7.AH.18.244; 7.AH.18.243;7.AH.18.247; 7.AH.26.157; 7.AH.26.158; 7.AH.26.196; 7.AH.26.223;7.AH.26.240; 7.AH.26.244; 7.AH.26.243; 7.AH.26.247; 7.AH.27.157;7.AH.27.158; 7.AH.27.196; 7.AH.27.223; 7.AH.27.240; 7.AH.27.244;7.AH.27.243; 7.AH.27.247; 7.AH.29.157; 7.AH.29.158; 7.AH.29.196;7.AH.29.223; 7.AH.29.240; 7.AH.29.244; 7.AH.29.243; 7.AH.29.247;7.AH.54.157; 7.AH.54.158; 7.AH.54.196; 7.AH.54.223; 7.AH.54.240;7.AH.54.244; 7.AH.54.243; 7.AH.54.247; 7.AH.55.157; 7.AH.55.158;7.AH.55.196; 7.AH.55.223; 7.AH.55.240; 7.AH.55.244; 7.AH.55.243;7.AH.55.247; 7.AH.56.157; 7.AH.56.158; 7.AH.56.196; 7.AH.56.223;7.AH.56.240; 7.AH.56.244; 7.AH.56.243; 7.AH.56.247; 7.AH.157.157;7.AH.157.158; 7.AH.157.196; 7.AH.157.223; 7.AH.157.240; 7.AH.157.244;7.AH.157.243; 7.AH.157.247; 7.AH.196.157; 7.AH.196.158; 7.AH.196.196;7.AH.196.223; 7.AH.196.240; 7.AH.196.244; 7.AH.196.243; 7.AH.196.247;7.AH.223.157; 7.AH.223.158; 7.AH.223.196; 7.AH.223.223; 7.AH.223.240;7.AH.223.244; 7.AH.223.243; 7.AH.223.247; 7.AH.240.157; 7.AH.240.158;7.AH.240.196; 7.AH.240.223; 7.AH.240.240; 7.AH.240.244; 7.AH.240.243;7.AH.240.247; 7.AH.244.157; 7.AH.244.158; 7.AH.244.196; 7.AH.244.223;7.AH.244.240; 7.AH.244.244; 7.AH.244.243; 7.AH.244.247; 7.AH.247.157;7.AH.247.158; 7.AH.247.196; 7.AH.247.223; 7.AH.247.240; 7.AH.247.244;7.AH.247.243; 7.AH.247.247; Prodrugs of 7.AJ 7.AJ.4.157; 7.AJ.4.158;7.AJ.4.196; 7.AJ.4.223; 7.AJ.4.240; 7.AJ.4.244; 7.AJ.4.243; 7.AJ.4.247;7.AJ.5.157; 7.AJ.5.158; 7.AJ.5.196; 7.AJ.5.223; 7.AJ.5.240; 7.AJ.5.244;7.AJ.5.243; 7.AJ.5.247; 7.AJ.7.157; 7.AJ.7.158; 7.AJ.7.196; 7.AJ.7.223;7.AJ.7.240; 7.AJ.7.244; 7.AJ.7.243; 7.AJ.7.247; 7.AJ.15.157;7.AJ.15.158; 7.AJ.15.196; 7.AJ.15.223; 7.AJ.15.240; 7.AJ.15.244;7.AJ.15.243; 7.AJ.15.247; 7.AJ.16.157; 7.AJ.16.158; 7.AJ.16.196;7.AJ.16.223; 7.AJ.16.240; 7.AJ.16.244; 7.AJ.16.243; 7.AJ.16.247;7.AJ.18.157; 7.AJ.18.158; 7.AJ.18.196; 7.AJ.18.223; 7.AJ.18.240;7.AJ.18.244; 7.AJ.18.243; 7.AJ.18.247; 7.AJ.26.157; 7.AJ.26.158;7.AJ.26.196; 7.AJ.26.223; 7.AJ.26.240; 7.AJ.26.244; 7.AJ.26.243;7.AJ.26.247; 7.AJ.27.157; 7.AJ.27.158; 7.AJ.27.196; 7.AJ.27.223;7.AJ.27.240; 7.AJ.27.244; 7.AJ.27.243; 7.AJ.27.247; 7.AJ.29.157;7.AJ.29.158; 7.AJ.29.196; 7.AJ.29.223; 7.AJ.29.240; 7.AJ.29.244;7.AJ.29.243; 7.AJ.29.247; 7.AJ.54.157; 7.AJ.54.158; 7.AJ.54.196;7.AJ.54.223; 7.AJ.54.240; 7.AJ.54.244; 7.AJ.54.243; 7.AJ.54.247;7.AJ.55.157; 7.AJ.55.158; 7.AJ.55.196; 7.AJ.55.223; 7.AJ.55.240;7.AJ.55.244; 7.AJ.55.243; 7.AJ.55.247; 7.AJ.56.157; 7.AJ.56.158;7.AJ.56.196; 7.AJ.56.223; 7.AJ.56.240; 7.AJ.56.244; 7.AJ.56.243;7.AJ.56.247; 7.AJ.157.157; 7.AJ.157.158; 7.AJ.157.196; 7.AJ.157.223;7.AJ.157.240; 7.AJ.157.244; 7.AJ.157.243; 7.AJ.157.247; 7.AJ.196.157;7.AJ.196.158; 7.AJ.196.196; 7.AJ.196.223; 7.AJ.196.240; 7.AJ.196.244;7.AJ.196.243; 7.AJ.196.247; 7.AJ.223.157; 7.AJ.223.158; 7.AJ.223.196;7.AJ.223.223; 7.AJ.223.240; 7.AJ.223.244; 7.AJ.223.243; 7.AJ.223.247;7.AJ.240.157; 7.AJ.240.158; 7.AJ.240.196; 7.AJ.240.223; 7.AJ.240.240;7.AJ.240.244; 7.AJ.240.243; 7.AJ.240.247; 7.AJ.244.157; 7.AJ.244.158;7.AJ.244.196; 7.AJ.244.223; 7.AJ.244.240; 7.AJ.244.244; 7.AJ.244.243;7.AJ.244.247; 7.AJ.247.157; 7.AJ.247.158; 7.AJ.247.196; 7.AJ.247.223;7.AJ.247.240; 7.AJ.247.244; 7.AJ.247.243; 7.AJ.247.247; Prodrugs of 7.AN7.AN.4.157; 7.AN.4.158; 7.AN.4.196; 7.AN.4.223; 7.AN.4.240; 7.AN.4.244;7.AN.4.243; 7.AN.4.247; 7.AN.5.157; 7.AN.5.158; 7.AN.5.196; 7.AN.5.223;7.AN.5.240; 7.AN.5.244; 7.AN.5.243; 7.AN.5.247; 7.AN.7.157; 7.AN.7.158;7.AN.7.196; 7.AN.7.223; 7.AN.7.240; 7.AN.7.244; 7.AN.7.243; 7.AN.7.247;7.AN.15.157; 7.AN.15.158; 7.AN.15.196; 7.AN.15.223; 7.AN.15.240;7.AN.15.244; 7.AN.15.243; 7.AN.15.247; 7.AN.16.157; 7.AN.16.158;7.AN.16.196; 7.AN.16.223; 7.AN.16.240; 7.AN.16.244; 7.AN.16.243;7.AN.16.247; 7.AN.18.157; 7.AN.18.158; 7.AN.18.196; 7.AN.18.223;7.AN.18.240; 7.AN.18.244; 7.AN.18.243; 7.AN.18.247; 7.AN.26.157;7.AN.26.158; 7.AN.26.196; 7.AN.26.223; 7.AN.26.240; 7.AN.26.244;7.AN.26.243; 7.AN.26.247; 7.AN.27.157; 7.AN.27.158; 7.AN.27.196;7.AN.27.223; 7.AN.27.240; 7.AN.27.244; 7.AN.27.243; 7.AN.27.247;7.AN.29.157; 7.AN.29.158; 7.AN.29.196; 7.AN.29.223; 7.AN.29.240;7.AN.29.244; 7.AN.29.243; 7.AN.29.247; 7.AN.54.157; 7.AN.54.158;7.AN.54.196; 7.AN.54.223; 7.AN.54.240; 7.AN.54.244; 7.AN.54.243;7.AN.54.247; 7.AN.55.157; 7.AN.55.158; 7.AN.55.196; 7.AN.55.223;7.AN.55.240; 7.AN.55.244; 7.AN.55.243; 7.AN.55.247; 7.AN.56.157;7.AN.56.158; 7.AN.56.196; 7.AN.56.223; 7.AN.56.240; 7.AN.56.244;7.AN.56.243; 7.AN.56.247; 7.AN.157.157; 7.AN.157.158; 7.AN.157.196;7.AN.157.223; 7.AN.157.240; 7.AN.157.244; 7.AN.157.243; 7.AN.157.247;7.AN.196.157; 7.AN.196.158; 7.AN.196.196; 7.AN.196.223; 7.AN.196.240;7.AN.196.244; 7.AN.196.243; 7.AN.196.247; 7.AN.223.157; 7.AN.223.158;7.AN.223.196; 7.AN.223.223; 7.AN.223.240; 7.AN.223.244; 7.AN.223.243;7.AN.223.247; 7.AN.240.157; 7.AN.240.158; 7.AN.240.196; 7.AN.240.223;7.AN.240.240; 7.AN.240.244; 7.AN.240.243; 7.AN.240.247; 7.AN.244.157;7.AN.244.158; 7.AN.244.196; 7.AN.244.223; 7.AN.244.240; 7.AN.244.244;7.AN.244.243; 7.AN.244.247; 7.AN.247.157; 7.AN.247.158; 7.AN.247.196;7.AN.247.223; 7.AN.247.240; 7.AN.247.244; 7.AN.247.243; 7.AN.247.247;Prodrugs of 7.AP 7.AP.4.157; 7.AP.4.158; 7.AP.4.196; 7.AP.4.223;7.AP.4.240; 7.AP.4.244; 7.AP.4.243; 7.AP.4.247; 7.AP.5.157; 7.AP.5.158;7.AP.5.196; 7.AP.5.223; 7.AP.5.240; 7.AP.5.244; 7.AP.5.243; 7.AP.5.247;7.AP.7.157; 7.AP.7.158; 7.AP.7.196; 7.AP.7.223; 7.AP.7.240; 7.AP.7.244;7.AP.7.243; 7.AP.7.247; 7.AP.15.157; 7.AP.15.158; 7.AP.15.196;7.AP.15.223; 7.AP.15.240; 7.AP.15.244; 7.AP.15.243; 7.AP.15.247;7.AP.16.157; 7.AP.16.158; 7.AP.16.196; 7.AP.16.223; 7.AP.16.240;7.AP.16.244; 7.AP.16.243; 7.AP.16.247; 7.AP.18.157; 7.AP.18.158;7.AP.18.196; 7.AP.18.223; 7.AP.18.240; 7.AP.18.244; 7.AP.18.243;7.AP.18.247; 7.AP.26.157; 7.AP.26.158; 7.AP.26.196; 7.AP.26.223;7.AP.26.240; 7.AP.26.244; 7.AP.26.243; 7.AP.26.247; 7.AP.27.157;7.AP.27.158; 7.AP.27.196; 7.AP.27.223; 7.AP.27.240; 7.AP.27.244;7.AP.27.243; 7.AP.27.247; 7.AP.29.157; 7.AP.29.158; 7.AP.29.196;7.AP.29.223; 7.AP.29.240; 7.AP.29.244; 7.AP.29.243; 7.AP.29.247;7.AP.54.157; 7.AP.54.158; 7.AP.54.196; 7.AP.54.223; 7.AP.54.240;7.AP.54.244; 7.AP.54.243; 7.AP.54.247; 7.AP.55.157; 7.AP.55.158;7.AP.55.196; 7.AP.55.223; 7.AP.55.240; 7.AP.55.244; 7.AP.55.243;7.AP.55.247; 7.AP.56.157; 7.AP.56.158; 7.AP.56.196; 7.AP.56.223;7.AP.56.240; 7.AP.56.244; 7.AP.56.243; 7.AP.56.247; 7.AP.157.157;7.AP.157.158; 7.AP.157.196; 7.AP.157.223; 7.AP.157.240; 7.AP.157.244;7.AP.157.243; 7.AP.157.247; 7.AP.196.157; 7.AP.196.158; 7.AP.196.196;7.AP.196.223; 7.AP.196.240; 7.AP.196.244; 7.AP.196.243; 7.AP.196.247;7.AP.223.157; 7.AP.223.158; 7.AP.223.196; 7.AP.223.223; 7.AP.223.240;7.AP.223.244; 7.AP.223.243; 7.AP.223.247; 7.AP.240.157; 7.AP.240.158;7.AP.240.196; 7.AP.240.223; 7.AP.240.240; 7.AP.240.244; 7.AP.240.243;7.AP.240.247; 7.AP.244.157; 7.AP.244.158; 7.AP.244.196; 7.AP.244.223;7.AP.244.240; 7.AP.244.244; 7.AP.244.243; 7.AP.244.247; 7.AP.247.157;7.AP.247.158; 7.AP.247.196; 7.AP.247.223; 7.AP.247.240; 7.AP.247.244;7.AP.247.243; 7.AP.247.247; Prodrugs of 7.AZ 7.AZ.4.157; 7.AZ.4.158;7.AZ.4.196; 7.AZ.4.223; 7.AZ.4.240; 7.AZ.4.244; 7.AZ.4.243; 7.AZ.4.247;7.AZ.5.157; 7.AZ.5.158; 7.AZ.5.196; 7.AZ.5.223; 7.AZ.5.240; 7.AZ.5.244;7.AZ.5.243; 7.AZ.5.247; 7.AZ.7.157; 7.AZ.7.158; 7.AZ.7.196; 7.AZ.7.223;7.AZ.7.240; 7.AZ.7.244; 7.AZ.7.243; 7.AZ.7.247; 7.AZ.15.157;7.AZ.15.158; 7.AZ.15.196; 7.AZ.15.223; 7.AZ.15.240; 7.AZ.15.244;7.AZ.15.243; 7.AZ.15.247; 7.AZ.16.157; 7.AZ.16.158; 7.AZ.16.196;7.AZ.16.223; 7.AZ.16.240; 7.AZ.16.244; 7.AZ.16.243; 7.AZ.16.247;7.AZ.18.157; 7.AZ.18.158; 7.AZ.18.196; 7.AZ.18.223; 7.AZ.18.240;7.AZ.18.244; 7.AZ.18.243; 7.AZ.18.247; 7.AZ.26.157; 7.AZ.26.158;7.AZ.26.196; 7.AZ.26.223; 7.AZ.26.240; 7.AZ.26.244; 7.AZ.26.243;7.AZ.26.247; 7.AZ.27.157; 7.AZ.27.158; 7.AZ.27.196; 7.AZ.27.223;7.AZ.27.240; 7.AZ.27.244; 7.AZ.27.243; 7.AZ.27.247; 7.AZ.29.157;7.AZ.29.158; 7.AZ.29.196; 7.AZ.29.223; 7.AZ.29.240; 7.AZ.29.244;7.AZ.29.243; 7.AZ.29.247; 7.AZ.54.157; 7.AZ.54.158; 7.AZ.54.196;7.AZ.54.223; 7.AZ.54.240; 7.AZ.54.244; 7.AZ.54.243; 7.AZ.54.247;7.AZ.55.157; 7.AZ.55.158; 7.AZ.55.196; 7.AZ.55.223; 7.AZ.55.240;7.AZ.55.244; 7.AZ.55.243; 7.AZ.55.247; 7.AZ.56.157; 7.AZ.56.158;7.AZ.56.196; 7.AZ.56.223; 7.AZ.56.240; 7.AZ.56.244; 7.AZ.56.243;7.AZ.56.247; 7.AZ.157.157; 7.AZ.157.158; 7.AZ.157.196; 7.AZ.157.223;7.AZ.157.240; 7.AZ.157.244; 7.AZ.157.243; 7.AZ.157.247; 7.AZ.196.157;7.AZ.196.158; 7.AZ.196.196; 7.AZ.196.223; 7.AZ.196.240; 7.AZ.196.244;7.AZ.196.243; 7.AZ.196.247; 7.AZ.223.157; 7.AZ.223.158; 7.AZ.223.196;7.AZ.223.223; 7.AZ.223.240; 7.AZ.223.244; 7.AZ.223.243; 7.AZ.223.247;7.AZ.240.157; 7.AZ.240.158; 7.AZ.240.196; 7.AZ.240.223; 7.AZ.240.240;7.AZ.240.244; 7.AZ.240.243; 7.AZ.240.247; 7.AZ.244.157; 7.AZ.244.158;7.AZ.244.196; 7.AZ.244.223; 7.AZ.244.240; 7.AZ.244.244; 7.AZ.244.243;7.AZ.244.247; 7.AZ.247.157; 7.AZ.247.158; 7.AZ.247.196; 7.AZ.247.223;7.AZ.247.240; 7.AZ.247.244; 7.AZ.247.243; 7.AZ.247.247; Prodrugs of 7.BF7.BF.4.157; 7.BF.4.158; 7.BF.4.196; 7.BF.4.223; 7.BF.4.240; 7.BF.4.244;7.BF.4.243; 7.BF.4.247; 7.BF.5.157; 7.BF.5.158; 7.BF.5.196; 7.BF.5.223;7.BF.5.240; 7.BF.5.244; 7.BF.5.243; 7.BF.5.247; 7.BF.7.157; 7.BF.7.158;7.BF.7.196; 7.BF.7.223; 7.BF.7.240; 7.BF.7.244; 7.BF.7.243; 7.BF.7.247;7.BF.15.157; 7.BF.15.158; 7.BF.15.196; 7.BF.15.223; 7.BF.15.240;7.BF.15.244; 7.BF.15.243; 7.BF.15.247; 7.BF.16.157; 7.BF.16.158;7.BF.16.196; 7.BF.16.223; 7.BF.16.240; 7.BF.16.244; 7.BF.16.243;7.BF.16.247; 7.BF.18.157; 7.BF.18.158; 7.BF.18.196; 7.BF.18.223;7.BF.18.240; 7.BF.18.244; 7.BF.18.243; 7.BF.18.247; 7.BF.26.157;7.BF.26.158; 7.BF.26.196; 7.BF.26.223; 7.BF.26.240; 7.BF.26.244;7.BF.26.243; 7.BF.26.247; 7.BF.27.157; 7.BF.27.158; 7.BF.27.196;7.BF.27.223; 7.BF.27.240; 7.BF.27.244; 7.BF.27.243; 7.BF.27.247;7.BF.29.157; 7.BF.29.158; 7.BF.29.196; 7.BF.29.223; 7.BF.29.240;7.BF.29.244; 7.BF.29.243; 7.BF.29.247; 7.BF.54.157; 7.BF.54.158;7.BF.54.196; 7.BF.54.223; 7.BF.54.240; 7.BF.54.244; 7.BF.54.243;7.BF.54.247; 7.BF.55.157; 7.BF.55.158; 7.BF.55.196; 7.BF.55.223;7.BF.55.240; 7.BF.55.244; 7.BF.55.243; 7.BF.55.247; 7.BF.56.157;7.BF.56.158; 7.BF.56.196; 7.BF.56.223; 7.BF.56.240; 7.BF.56.244;7.BF.56.243; 7.BF.56.247; 7.BF.157.157; 7.BF.157.158; 7.BF.157.196;7.BF.157.223; 7.BF.157.240; 7.BF.157.244; 7.BF.157.243; 7.BF.157.247;7.BF.196.157; 7.BF.196.158; 7.BF.196.196; 7.BF.196.223; 7.BF.196.240;7.BF.196.244; 7.BF.196.243; 7.BF.196.247; 7.BF.223.157; 7.BF.223.158;7.BF.223.196; 7.BF.223.223; 7.BF.223.240; 7.BF.223.244; 7.BF.223.243;7.BF.223.247; 7.BF.240.157; 7.BF.240.158; 7.BF.240.196; 7.BF.240.223;7.BF.240.240; 7.BF.240.244; 7.BF.240.243; 7.BF.240.247; 7.BF.244.157;7.BF.244.158; 7.BF.244.196; 7.BF.244.223; 7.BF.244.240; 7.BF.244.244;7.BF.244.243; 7.BF.244.247; 7.BF.247.157; 7.BF.247.158; 7.BF.247.196;7.BF.247.223; 7.BF.247.240; 7.BF.247.244; 7.BF.247.243; 7.BF.247.247;Prodrugs of 7.CI 7.CI.4.157; 7.CI.4.158; 7.CI.4.196; 7.CI.4.223;7.CI.4.240; 7.CI.4.244; 7.CI.4.243; 7.CI.4.247; 7.CI.5.157; 7.CI.5.158;7.CI.5.196; 7.CI.5.223; 7.CI.5.240; 7.CI.5.244; 7.CI.5.243; 7.CI.5.247;7.CI.7.157; 7.CI.7.158; 7.CI.7.196; 7.CI.7.223; 7.CI.7.240; 7.CI.7.244;7.CI.7.243; 7.CI.7.247; 7.CI.15.157; 7.CI.15.158; 7.CI.15.196;7.CI.15.223; 7.CI.15.240; 7.CI.15.244; 7.CI.15.243; 7.CI.15.247;7.CI.16.157; 7.CI.16.158; 7.CI.16.196; 7.CI.16.223; 7.CI.16.240;7.CI.16.244; 7.CI.16.243; 7.CI.16.247; 7.CI.18.157; 7.CI.18.158;7.CI.18.196; 7.CI.18.223; 7.CI.18.240; 7.CI.18.244; 7.CI.18.243;7.CI.18.247; 7.CI.26.157; 7.CI.26.158; 7.CI.26.196; 7.CI.26.223;7.CI.26.240; 7.CI.26.244; 7.CI.26.243; 7.CI.26.247; 7.CI.27.157;7.CI.27.158; 7.CI.27.196; 7.CI.27.223; 7.CI.27.240; 7.CI.27.244;7.CI.27.243; 7.CI.27.247; 7.CI.29.157; 7.CI.29.158; 7.CI.29.196;7.CI.29.223; 7.CI.29.240; 7.CI.29.244; 7.CI.29.243; 7.CI.29.247;7.CI.54.157; 7.CI.54.158; 7.CI.54.196; 7.CI.54.223; 7.CI.54.240;7.CI.54.244; 7.CI.54.243; 7.CI.54.247; 7.CI.55.157; 7.CI.55.158;7.CI.55.196; 7.CI.55.223; 7.CI.55.240; 7.CI.55.244; 7.CI.55.243;7.CI.55.247; 7.CI.56.157; 7.CI.56.158; 7.CI.56.196; 7.CI.56.223;7.CI.56.240; 7.CI.56.244; 7.CI.56.243; 7.CI.56.247; 7.CI.157.157;7.CI.157.158; 7.CI.157.196; 7.CI.157.223; 7.CI.157.240; 7.CI.157.244;7.CI.157.243; 7.CI.157.247; 7.CI.196.157; 7.CI.196.158; 7.CI.196.196;7.CI.196.223; 7.CI.196.240; 7.CI.196.244; 7.CI.196.243; 7.CI.196.247;7.CI.223.157; 7.CI.223.158; 7.CI.223.196; 7.CI.223.223; 7.CI.223.240;7.CI.223.244; 7.CI.223.243; 7.CI.223.247; 7.CI.240.157; 7.CI.240.158;7.CI.240.196; 7.CI.240.223; 7.CI.240.240; 7.CI.240.244; 7.CI.240.243;7.CI.240.247; 7.CI.244.157; 7.CI.244.158; 7.CI.244.196; 7.CI.244.223;7.CI.244.240; 7.CI.244.244; 7.CI.244.243; 7.CI.244.247; 7.CI.247.157;7.CI.247.158; 7.CI.247.196; 7.CI.247.223; 7.CI.247.240; 7.CI.247.244;7.CI.247.243; 7.CI.247.247; Prodrugs of 7.CO 7.CO.4.157; 7.CO.4.158;7.CO.4.196; 7.CO.4.223; 7.CO.4.240; 7.CO.4.244; 7.CO.4.243; 7.CO.4.247;7.CO.5.157; 7.CO.5.158; 7.CO.5.196; 7.CO.5.223; 7.CO.5.240; 7.CO.5.244;7.CO.5.243; 7.CO.5.247; 7.CO.7.157; 7.CO.7.158; 7.CO.7.196; 7.CO.7.223;7.CO.7.240; 7.CO.7.244; 7.CO.7.243; 7.CO.7.247; 7.CO.15.157;7.CO.15.158; 7.CO.15.196; 7.CO.15.223; 7.CO.15.240; 7.CO.15.244;7.CO.15.243; 7.CO.15.247; 7.CO.16.157; 7.CO.16.158; 7.CO.16.196;7.CO.16.223; 7.CO.16.240; 7.CO.16.244; 7.CO.16.243; 7.CO.16.247;7.CO.18.157; 7.CO.18.158; 7.CO.18.196; 7.CO.18.223; 7.CO.18.240;7.CO.18.244; 7.CO.18.243; 7.CO.18.247; 7.CO.26.157; 7.CO.26.158;7.CO.26.196; 7.CO.26.223; 7.CO.26.240; 7.CO.26.244; 7.CO.26.243;7.CO.26.247; 7.CO.27.157; 7.CO.27.158; 7.CO.27.196; 7.CO.27.223;7.CO.27.240; 7.CO.27.244; 7.CO.27.243; 7.CO.27.247; 7.CO.29.157;7.CO.29.158; 7.CO.29.196; 7.CO.29.223; 7.CO.29.240; 7.CO.29.244;7.CO.29.243; 7.CO.29.247; 7.CO.54.157; 7.CO.54.158; 7.CO.54.196;7.CO.54.223; 7.CO.54.240; 7.CO.54.244; 7.CO.54.243; 7.CO.54.247;7.CO.55.157; 7.CO.55.158; 7.CO.55.196; 7.CO.55.223; 7.CO.55.240;7.CO.55.244; 7.CO.55.243; 7.CO.55.247; 7.CO.56.157; 7.CO.56.158;7.CO.56.196; 7.CO.56.223; 7.CO.56.240; 7.CO.56.244; 7.CO.56.243;7.CO.56.247; 7.CO.157.157; 7.CO.157.158; 7.CO.157.196; 7.CO.157.223;7.CO.157.240; 7.CO.157.244; 7.CO.157.243; 7.CO.157.247; 7.CO.196.157;7.CO.196.158; 7.CO.196.196; 7.CO.196.223; 7.CO.196.240; 7.CO.196.244;7.CO.196.243; 7.CO.196.247; 7.CO.223.157; 7.CO.223.158; 7.CO.223.196;7.CO.223.223; 7.CO.223.240; 7.CO.223.244; 7.CO.223.243; 7.CO.223.247;7.CO.240.157; 7.CO.240.158; 7.CO.240.196; 7.CO.240.223; 7.CO.240.240;7.CO.240.244; 7.CO.240.243; 7.CO.240.247; 7.CO.244.157; 7.CO.244.158;7.CO.244.196; 7.CO.244.223; 7.CO.244.240; 7.CO.244.244; 7.CO.244.243;7.CO.244.247; 7.CO.4.157; 7.CO.4.158; 7.CO.4.196; 7.CO.4.223;7.CO.4.240; 7.CO.4.244; 7.CO.4.243; 7.CO.4.247; Prodrugs of 8.AH8.AH.4.157; 8.AH.4.158; 8.AH.4.196; 8.AH.4.223; 8.AH.4.240; 8.AH.4.244;8.AH.4.243; 8.AH.4.247; 8.AH.5.157; 8.AH.5.158; 8.AH.5.196; 8.AH.5.223;8.AH.5.240; 8.AH.5.244; 8.AH.5.243; 8.AH.5.247; 8.AH.7.157; 8.AH.7.158;8.AH.7.196; 8.AH.7.223; 8.AH.7.240; 8.AH.7.244; 8.AH.7.243; 8.AH.7.247;8.AH.15.157; 8.AH.15.158; 8.AH.15.196; 8.AH.15.223; 8.AH.15.240;8.AH.15.244; 8.AH.15.243; 8.AH.15.247; 8.AH.16.157; 8.AH.16.158;8.AH.16.196; 8.AH.16.223; 8.AH.16.240; 8.AH.16.244; 8.AH.16.243;8.AH.16.247; 8.AH.18.157; 8.AH.18.158; 8.AH.18.196; 8.AH.18.223;8.AH.18.240; 8.AH.18.244; 8.AH.18.243; 8.AH.18.247; 8.AH.26.157;8.AH.26.158; 8.AH.26.196; 8.AH.26.223; 8.AH.26.240; 8.AH.26.244;8.AH.26.243; 8.AH.26.247; 8.AH.27.157; 8.AH.27.158; 8.AH.27.196;8.AH.27.223; 8.AH.27.240; 8.AH.27.244; 8.AH.27.243; 8.AH.27.247;8.AH.29.157; 8.AH.29.158; 8.AH.29.196; 8.AH.29.223; 8.AH.29.240;8.AH.29.244; 8.AH.29.243; 8.AH.29.247; 8.AH.54.157; 8.AH.54.158;8.AH.54.196; 8.AH.54.223; 8.AH.54.240; 8.AH.54.244; 8.AH.54.243;8.AH.54.247; 8.AH.55.157; 8.AH.55.158; 8.AH.55.196; 8.AH.55.223;8.AH.55.240; 8.AH.55.244; 8.AH.55.243; 8.AH.55.247; 8.AH.56.157;8.AH.56.158; 8.AH.56.196; 8.AH.56.223; 8.AH.56.240; 8.AH.56.244;8.AH.56.243; 8.AH.56.247; 8.AH.157.157; 8.AH.157.158; 8.AH.157.196;8.AH.157.223; 8.AH.157.240; 8.AH.157.244; 8.AH.157.243; 8.AH.157.247;8.AH.196.157; 8.AH.196.158; 8.AH.196.196; 8.AH.196.223; 8.AH.196.240;8.AH.196.244; 8.AH.196.243; 8.AH.196.247; 8.AH.223.157; 8.AH.223.158;8.AH.223.196; 8.AH.223.223; 8.AH.223.240; 8.AH.223.244; 8.AH.223.243;8.AH.223.247; 8.AH.240.157; 8.AH.240.158; 8.AH.240.196; 8.AH.240.223;8.AH.240.240; 8.AH.240.244; 8.AH.240.243; 8.AH.240.247; 8.AH.244.157;8.AH.244.158; 8.AH.244.196; 8.AH.244.223; 8.AH.244.240; 8.AH.244.244;8.AH.244.243; 8.AH.244.247; 8.AH.247.157; 8.AH.247.158; 8.AH.247.196;8.AH.247.223; 8.AH.247.240; 8.AH.247.244; 8.AH.247.243; 8.AH.247.247;Prodrugs of 8.AJ 8.AJ.4.157; 8.AJ.4.158; 8.AJ.4.196; 8.AJ.4.223;8.AJ.4.240; 8.AJ.4.244; 8.AJ.4.243; 8.AJ.4.247; 8.AJ.5.157; 8.AJ.5.158;8.AJ.5.196; 8.AJ.5.223; 8.AJ.5.240; 8.AJ.5.244; 8.AJ.5.243; 8.AJ.5.247;8.AJ.7.157; 8.AJ.7.158; 8.AJ.7.196; 8.AJ.7.223; 8.AJ.7.240; 8.AJ.7.244;8.AJ.7.243; 8.AJ.7.247; 8.AJ.15.157; 8.AJ.15.158; 8.AJ.15.196;8.AJ.15.223; 8.AJ.15.240; 8.AJ.15.244; 8.AJ.15.243; 8.AJ.15.247;8.AJ.16.157; 8.AJ.16.158; 8.AJ.16.196; 8.AJ.16.223; 8.AJ.16.240;8.AJ.16.244; 8.AJ.16.243; 8.AJ.16.247; 8.AJ.18.157; 8.AJ.18.158;8.AJ.18.196; 8.AJ.18.223; 8.AJ.18.240; 8.AJ.18.244; 8.AJ.18.243;8.AJ.18.247; 8.AJ.26.157; 8.AJ.26.158; 8.AJ.26.196; 8.AJ.26.223;8.AJ.26.240; 8.AJ.26.244; 8.AJ.26.243; 8.AJ.26.247; 8.AJ.27.157;8.AJ.27.158; 8.AJ.27.196; 8.AJ.27.223; 8.AJ.27.240; 8.AJ.27.244;8.AJ.27.243; 8.AJ.27.247; 8.AJ.29.157; 8.AJ.29.158; 8.AJ.29.196;8.AJ.29.223; 8.AJ.29.240; 8.AJ.29.244; 8.AJ.29.243; 8.AJ.29.247;8.AJ.54.157; 8.AJ.54.158; 8.AJ.54.196; 8.AJ.54.223; 8.AJ.54.240;8.AJ.54.244; 8.AJ.54.243; 8.AJ.54.247; 8.AJ.55.157; 8.AJ.55.158;8.AJ.55.196; 8.AJ.55.223; 8.AJ.55.240; 8.AJ.55.244; 8.AJ.55.243;8.AJ.55.247; 8.AJ.56.157; 8.AJ.56.158; 8.AJ.56.196; 8.AJ.56.223;8.AJ.56.240; 8.AJ.56.244; 8.AJ.56.243; 8.AJ.56.247; 8.AJ.157.157;8.AJ.157.158; 8.AJ.157.196; 8.AJ.157.223; 8.AJ.157.240; 8.AJ.157.244;8.AJ.157.243; 8.AJ.157.247; 8.AJ.196.157; 8.AJ.196.158; 8.AJ.196.196;8.AJ.196.223; 8.AJ.196.240; 8.AJ.196.244; 8.AJ.196.243; 8.AJ.196.247;8.AJ.223.157; 8.AJ.223.158; 8.AJ.223.196; 8.AJ.223.223; 8.AJ.223.240;8.AJ.223.244; 8.AJ.223.243; 8.AJ.223.247; 8.AJ.240.157; 8.AJ.240.158;8.AJ.240.196; 8.AJ.240.223; 8.AJ.240.240; 8.AJ.240.244; 8.AJ.240.243;8.AJ.240.247; 8.AJ.244.157; 8.AJ.244.158; 8.AJ.244.196; 8.AJ.244.223;8.AJ.244.240; 8.AJ.244.244; 8.AJ.244.243; 8.AJ.244.247; 8.AJ.247.157;8.AJ.247.158; 8.AJ.247.196; 8.AJ.247.223; 8.AJ.247.240; 8.AJ.247.244;8.AJ.247.243; 8.AJ.247.247; Prodrugs of 8.AN 8.AN.4.157; 8.AN.4.158;8.AN.4.196; 8.AN.4.223; 8.AN.4.240; 8.AN.4.244; 8.AN.4.243; 8.AN.4.247;8.AN.5.157; 8.AN.5.158; 8.AN.5.196; 8.AN.5.223; 8.AN.5.240; 8.AN.5.244;8.AN.5.243; 8.AN.5.247; 8.AN.7.157; 8.AN.7.158; 8.AN.7.196; 8.AN.7.223;8.AN.7.240; 8.AN.7.244; 8.AN.7.243; 8.AN.7.247; 8.AN.15.157;8.AN.15.158; 8.AN.15.196; 8.AN.15.223; 8.AN.15.240; 8.AN.15.244;8.AN.15.243; 8.AN.15.247; 8.AN.16.157; 8.AN.16.158; 8.AN.16.196;8.AN.16.223; 8.AN.16.240; 8.AN.16.244; 8.AN.16.243; 8.AN.16.247;8.AN.18.157; 8.AN.18.158; 8.AN.18.196; 8.AN.18.223; 8.AN.18.240;8.AN.18.244; 8.AN.18.243; 8.AN.18.247; 8.AN.26.157; 8.AN.26.158;8.AN.26.196; 8.AN.26.223; 8.AN.26.240; 8.AN.26.244; 8.AN.26.243;8.AN.26.247; 8.AN.27.157; 8.AN.27.158; 8.AN.27.196; 8.AN.27.223;8.AN.27.240; 8.AN.27.244; 8.AN.27.243; 8.AN.27.247; 8.AN.29.157;8.AN.29.158; 8.AN.29.196; 8.AN.29.223; 8.AN.29.240; 8.AN.29.244;8.AN.29.243; 8.AN.29.247; 8.AN.54.157; 8.AN.54.158; 8.AN.54.196;8.AN.54.223; 8.AN.54.240; 8.AN.54.244; 8.AN.54.243; 8.AN.54.247;8.AN.55.157; 8.AN.55.158; 8.AN.55.196; 8.AN.55.223; 8.AN.55.240;8.AN.55.244; 8.AN.55.243; 8.AN.55.247; 8.AN.56.157; 8.AN.56.158;8.AN.56.196; 8.AN.56.223; 8.AN.56.240; 8.AN.56.244; 8.AN.56.243;8.AN.56.247; 8.AN.157.157; 8.AN.157.158; 8.AN.157.196; 8.AN.157.223;8.AN.157.240; 8.AN.157.244; 8.AN.157.243; 8.AN.157.247; 8.AN.196.157;8.AN.196.158; 8.AN.196.196; 8.AN.196.223; 8.AN.196.240; 8.AN.196.244;8.AN.196.243; 8.AN.196.247; 8.AN.223.157; 8.AN.223.158; 8.AN.223.196;8.AN.223.223; 8.AN.223.240; 8.AN.223.244; 8.AN.223.243; 8.AN.223.247;8.AN.240.157; 8.AN.240.158; 8.AN.240.196; 8.AN.240.223; 8.AN.240.240;8.AN.240.244; 8.AN.240.243; 8.AN.240.247; 8.AN.244.157; 8.AN.244.158;8.AN.244.196; 8.AN.244.223; 8.AN.244.240; 8.AN.244.244; 8.AN.244.243;8.AN.244.247; 8.AN.247.157; 8.AN.247.158; 8.AN.247.196; 8.AN.247.223;8.AN.247.240; 8.AN.247.244; 8.AN.247.243; 8.AN.247.247; Prodrugs of 8.AP8.AP.4.157; 8.AP.4.158; 8.AP.4.196; 8.AP.4.223; 8.AP.4.240; 8.AP.4.244;8.AP.4.243; 8.AP.4.247; 8.AP.5.157; 8.AP.5.158; 8.AP.5.196; 8.AP.5.223;8.AP.5.240; 8.AP.5.244; 8.AP.5.243; 8.AP.5.247; 8.AP.7.157; 8.AP.7.158;8.AP.7.196; 8.AP.7.223; 8.AP.7.240; 8.AP.7.244; 8.AP.7.243; 8.AP.7.247;8.AP.15.157; 8.AP.15.158; 8.AP.15.196; 8.AP.15.223; 8.AP.15.240;8.AP.15.244; 8.AP.15.243; 8.AP.15.247; 8.AP.16.157; 8.AP.16.158;8.AP.16.196; 8.AP.16.223; 8.AP.16.240; 8.AP.16.244; 8.AP.16.243;8.AP.16.247; 8.AP.18.157; 8.AP.18.158; 8.AP.18.196; 8.AP.18.223;8.AP.18.240; 8.AP.18.244; 8.AP.18.243; 8.AP.18.247; 8.AP.26.157;8.AP.26.158; 8.AP.26.196; 8.AP.26.223; 8.AP.26.240; 8.AP.26.244;8.AP.26.243; 8.AP.26.247; 8.AP.27.157; 8.AP.27.158; 8.AP.27.196;8.AP.27.223; 8.AP.27.240; 8.AP.27.244; 8.AP.27.243; 8.AP.27.247;8.AP.29.157; 8.AP.29.158; 8.AP.29.196; 8.AP.29.223; 8.AP.29.240;8.AP.29.244; 8.AP.29.243; 8.AP.29.247; 8.AP.54.157; 8.AP.54.158;8.AP.54.196; 8.AP.54.223; 8.AP.54.240; 8.AP.54.244; 8.AP.54.243;8.AP.54.247; 8.AP.55.157; 8.AP.55.158; 8.AP.55.196; 8.AP.55.223;8.AP.55.240; 8.AP.55.244; 8.AP.55.243; 8.AP.55.247; 8.AP.56.157;8.AP.56.158; 8.AP.56.196; 8.AP.56.223; 8.AP.56.240; 8.AP.56.244;8.AP.56.243; 8.AP.56.247; 8.AP.157.157; 8.AP.157.158; 8.AP.157.196;8.AP.157.223; 8.AP.157.240; 8.AP.157.244; 8.AP.157.243; 8.AP.157.247;8.AP.196.157; 8.AP.196.158; 8.AP.196.196; 8.AP.196.223; 8.AP.196.240;8.AP.196.244; 8.AP.196.243; 8.AP.196.247; 8.AP.223.157; 8.AP.223.158;8.AP.223.196; 8.AP.223.223; 8.AP.223.240; 8.AP.223.244; 8.AP.223.243;8.AP.223.247; 8.AP.240.157; 8.AP.240.158; 8.AP.240.196; 8.AP.240.223;8.AP.240.240; 8.AP.240.244; 8.AP.240.243; 8.AP.240.247; 8.AP.244.157;8.AP.244.158; 8.AP.244.196; 8.AP.244.223; 8.AP.244.240; 8.AP.244.244;8.AP.244.243; 8.AP.244.247; 8.AP.247.157; 8.AP.247.158; 8.AP.247.196;8.AP.247.223; 8.AP.247.240; 8.AP.247.244; 8.AP.247.243; 8.AP.247.247;Prodrugs of 8.AZ 8.AZ.4.157; 8.AZ.4.158; 8.AZ.4.196; 8.AZ.4.223;8.AZ.4.240; 8.AZ.4.244; 8.AZ.4.243; 8.AZ.4.247; 8.AZ.5.157; 8.AZ.5.158;8.AZ.5.196; 8.AZ.5.223; 8.AZ.5.240; 8.AZ.5.244; 8.AZ.5.243; 8.AZ.5.247;8.AZ.7.157; 8.AZ.7.158; 8.AZ.7.196; 8.AZ.7.223; 8.AZ.7.240; 8.AZ.7.244;8.AZ.7.243; 8.AZ.7.247; 8.AZ.15.157; 8.AZ.15.158; 8.AZ.15.196;8.AZ.15.223; 8.AZ.15.240; 8.AZ.15.244; 8.AZ.15.243; 8.AZ.15.247;8.AZ.16.157; 8.AZ.16.158; 8.AZ.16.196; 8.AZ.16.223; 8.AZ.16.240;8.AZ.16.244; 8.AZ.16.243; 8.AZ.16.247; 8.AZ.18.157; 8.AZ.18.158;8.AZ.18.196; 8.AZ.18.223; 8.AZ.18.240; 8.AZ.18.244; 8.AZ.18.243;8.AZ.18.247; 8.AZ.26.157; 8.AZ.26.158; 8.AZ.26.196; 8.AZ.26.223;8.AZ.26.240; 8.AZ.26.244; 8.AZ.26.243; 8.AZ.26.247; 8.AZ.27.157;8.AZ.27.158; 8.AZ.27.196; 8.AZ.27.223; 8.AZ.27.240; 8.AZ.27.244;8.AZ.27.243; 8.AZ.27.247; 8.AZ.29.157; 8.AZ.29.158; 8.AZ.29.196;8.AZ.29.223; 8.AZ.29.240; 8.AZ.29.244; 8.AZ.29.243; 8.AZ.29.247;8.AZ.54.157; 8.AZ.54.158; 8.AZ.54.196; 8.AZ.54.223; 8.AZ.54.240;8.AZ.54.244; 8.AZ.54.243; 8.AZ.54.247; 8.AZ.55.157; 8.AZ.55.158;8.AZ.55.196; 8.AZ.55.223; 8.AZ.55.240; 8.AZ.55.244; 8.AZ.55.243;8.AZ.55.247; 8.AZ.56.157; 8.AZ.56.158; 8.AZ.56.196; 8.AZ.56.223;8.AZ.56.240; 8.AZ.56.244; 8.AZ.56.243; 8.AZ.56.247; 8.AZ.157.157;8.AZ.157.158; 8.AZ.157.196; 8.AZ.157.223; 8.AZ.157.240; 8.AZ.157.244;8.AZ.157.243; 8.AZ.157.247; 8.AZ.196.157; 8.AZ.196.158; 8.AZ.196.196;8.AZ.196.223; 8.AZ.196.240; 8.AZ.196.244; 8.AZ.196.243; 8.AZ.196.247;8.AZ.223.157; 8.AZ.223.158; 8.AZ.223.196; 8.AZ.223.223; 8.AZ.223.240;8.AZ.223.244; 8.AZ.223.243; 8.AZ.223.247; 8.AZ.240.157; 8.AZ.240.158;8.AZ.240.196; 8.AZ.240.223; 8.AZ.240.240; 8.AZ.240.244; 8.AZ.240.243;8.AZ.240.247; 8.AZ.244.157; 8.AZ.244.158; 8.AZ.244.196; 8.AZ.244.223;8.AZ.244.240; 8.AZ.244.244; 8.AZ.244.243; 8.AZ.244.247; 8.AZ.247.157;8.AZ.247.158; 8.AZ.247.196; 8.AZ.247.223; 8.AZ.247.240; 8.AZ.247.244;8.AZ.247.243; 8.AZ.247.247; Prodrugs of 8.BF 8.BF.4.157; 8.BF.4.158;8.BF.4.196; 8.BF.4.223; 8.BF.4.240; 8.BF.4.244; 8.BF.4.243; 8.BF.4.247;8.BF.5.157; 8.BF.5.158; 8.BF.5.196; 8.BF.5.223; 8.BF.5.240; 8.BF.5.244;8.BF.5.243; 8.BF.5.247; 8.BF.7.157; 8.BF.7.158; 8.BF.7.196; 8.BF.7.223;8.BF.7.240; 8.BF.7.244; 8.BF.7.243; 8.BF.7.247; 8.BF.15.157;8.BF.15.158; 8.BF.15.196; 8.BF.15.223; 8.BF.15.240; 8.BF.15.244;8.BF.15.243; 8.BF.15.247; 8.BF.16.157; 8.BF.16.158; 8.BF.16.196;8.BF.16.223; 8.BF.16.240; 8.BF.16.244; 8.BF.16.243; 8.BF.16.247;8.BF.18.157; 8.BF.18.158; 8.BF.18.196; 8.BF.18.223; 8.BF.18.240;8.BF.18.244; 8.BF.18.243; 8.BF.18.247; 8.BF.26.157; 8.BF.26.158;8.BF.26.196; 8.BF.26.223; 8.BF.26.240; 8.BF.26.244; 8.BF.26.243;8.BF.26.247; 8.BF.27.157; 8.BF.27.158; 8.BF.27.196; 8.BF.27.223;8.BF.27.240; 8.BF.27.244; 8.BF.27.243; 8.BF.27.247; 8.BF.29.157;8.BF.29.158; 8.BF.29.196; 8.BF.29.223; 8.BF.29.240; 8.BF.29.244;8.BF.29.243; 8.BF.29.247; 8.BF.54.157; 8.BF.54.158; 8.BF.54.196;8.BF.54.223; 8.BF.54.240; 8.BF.54.244; 8.BF.54.243; 8.BF.54.247;8.BF.55.157; 8.BF.55.158; 8.BF.55.196; 8.BF.55.223; 8.BF.55.240;8.BF.55.244; 8.BF.55.243; 8.BF.55.247; 8.BF.56.157; 8.BF.56.158;8.BF.56.196; 8.BF.56.223; 8.BF.56.240; 8.BF.56.244; 8.BF.56.243;8.BF.56.247; 8.BF.157.157; 8.BF.157.158; 8.BF.157.196; 8.BF.157.223;8.BF.157.240; 8.BF.157.244; 8.BF.157.243; 8.BF.157.247; 8.BF.196.157;8.BF.196.158; 8.BF.196.196; 8.BF.196.223; 8.BF.196.240; 8.BF.196.244;8.BF.196.243; 8.BF.196.247; 8.BF.223.157; 8.BF.223.158; 8.BF.223.196;8.BF.223.223; 8.BF.223.240; 8.BF.223.244; 8.BF.223.243; 8.BF.223.247;8.BF.240.157; 8.BF.240.158; 8.BF.240.196; 8.BF.240.223; 8.BF.240.240;8.BF.240.244; 8.BF.240.243; 8.BF.240.247; 8.BF.244.157; 8.BF.244.158;8.BF.244.196; 8.BF.244.223; 8.BF.244.240; 8.BF.244.244; 8.BF.244.243;8.BF.244.247; 8.BF.247.157; 8.BF.247.158; 8.BF.247.196; 8.BF.247.223;8.BF.247.240; 8.BF.247.244; 8.BF.247.243; 8.BF.247.247; Prodrugs of 8.CI8.CI.4.157; 8.CI.4.158; 8.CI.4.196; 8.CI.4.223; 8.CI.4.240; 8.CI.4.244;8.CI.4.243; 8.CI.4.247; 8.CI.5.157; 8.CI.5.158; 8.CI.5.196; 8.CI.5.223;8.CI.5.240; 8.CI.5.244; 8.CI.5.243; 8.CI.5.247; 8.CI.7.157; 8.CI.7.158;8.CI.7.196; 8.CI.7.223; 8.CI.7.240; 8.CI.7.244; 8.CI.7.243; 8.CI.7.247;8.CI.15.157; 8.CI.15.158; 8.CI.15.196; 8.CI.15.223; 8.CI.15.240;8.CI.15.244; 8.CI.15.243; 8.CI.15.247; 8.CI.16.157; 8.CI.16.158;8.CI.16.196; 8.CI.16.223; 8.CI.16.240; 8.CI.16.244; 8.CI.16.243;8.CI.16.247; 8.CI.18.157; 8.CI.18.158; 8.CI.18.196; 8.CI.18.223;8.CI.18.240; 8.CI.18.244; 8.CI.18.243; 8.CI.18.247; 8.CI.26.157;8.CI.26.158; 8.CI.26.196; 8.CI.26.223; 8.CI.26.240; 8.CI.26.244;8.CI.26.243; 8.CI.26.247; 8.CI.27.157; 8.CI.27.158; 8.CI.27.196;8.CI.27.223; 8.CI.27.240; 8.CI.27.244; 8.CI.27.243; 8.CI.27.247;8.CI.29.157; 8.CI.29.158; 8.CI.29.196; 8.CI.29.223; 8.CI.29.240;8.CI.29.244; 8.CI.29.243; 8.CI.29.247; 8.CI.54.157; 8.CI.54.158;8.CI.54.196; 8.CI.54.223; 8.CI.54.240; 8.CI.54.244; 8.CI.54.243;8.CI.54.247; 8.CI.55.157; 8.CI.55.158; 8.CI.55.196; 8.CI.55.223;8.CI.55.240; 8.CI.55.244; 8.CI.55.243; 8.CI.55.247; 8.CI.56.157;8.CI.56.158; 8.CI.56.196; 8.CI.56.223; 8.CI.56.240; 8.CI.56.244;8.CI.56.243; 8.CI.56.247; 8.CI.157.157; 8.CI.157.158; 8.CI.157.196;8.CI.157.223; 8.CI.157.240; 8.CI.157.244; 8.CI.157.243; 8.CI.157.247;8.CI.196.157; 8.CI.196.158; 8.CI.196.196; 8.CI.196.223; 8.CI.196.240;8.CI.196.244; 8.CI.196.243; 8.CI.196.247; 8.CI.223.157; 8.CI.223.158;8.CI.223.196; 8.CI.223.223; 8.CI.223.240; 8.CI.223.244; 8.CI.223.243;8.CI.223.247; 8.CI.240.157; 8.CI.240.158; 8.CI.240.196; 8.CI.240.223;8.CI.240.240; 8.CI.240.244; 8.CI.240.243; 8.CI.240.247; 8.CI.244.157;8.CI.244.158; 8.CI.244.196; 8.CI.244.223; 8.CI.244.240; 8.CI.244.244;8.CI.244.243; 8.CI.244.247; 8.CI.247.157; 8.CI.247.158; 8.CI.247.196;8.CI.247.223; 8.CI.247.240; 8.CI.247.244; 8.CI.247.243; 8.CI.247.247;Prodrugs of 8.CO 8.CO.4.157; 8.CO.4.158; 8.CO.4.196; 8.CO.4.223;8.CO.4.240; 8.CO.4.244; 8.CO.4.243; 8.CO.4.247; 8.CO.5.157; 8.CO.5.158;8.CO.5.196; 8.CO.5.223; 8.CO.5.240; 8.CO.5.244; 8.CO.5.243; 8.CO.5.247;8.CO.7.157; 8.CO.7.158; 8.CO.7.196; 8.CO.7.223; 8.CO.7.240; 8.CO.7.244;8.CO.7.243; 8.CO.7.247; 8.CO.15.157; 8.CO.15.158; 8.CO.15.196;8.CO.15.223; 8.CO.15.240; 8.CO.15.244; 8.CO.15.243; 8.CO.15.247;8.CO.16.157; 8.CO.16.158; 8.CO.16.196; 8.CO.16.223; 8.CO.16.240;8.CO.16.244; 8.CO.16.243; 8.CO.16.247; 8.CO.18.157; 8.CO.18.158;8.CO.18.196; 8.CO.18.223; 8.CO.18.240; 8.CO.18.244; 8.CO.18.243;8.CO.18.247; 8.CO.26.157; 8.CO.26.158; 8.CO.26.196; 8.CO.26.223;8.CO.26.240; 8.CO.26.244; 8.CO.26.243; 8.CO.26.247; 8.CO.27.157;8.CO.27.158; 8.CO.27.196; 8.CO.27.223; 8.CO.27.240; 8.CO.27.244;8.CO.27.243; 8.CO.27.247; 8.CO.29.157; 8.CO.29.158; 8.CO.29.196;8.CO.29.223; 8.CO.29.240; 8.CO.29.244; 8.CO.29.243; 8.CO.29.247;8.CO.54.157; 8.CO.54.158; 8.CO.54.196; 8.CO.54.223; 8.CO.54.240;8.CO.54.244; 8.CO.54.243; 8.CO.54.247; 8.CO.55.157; 8.CO.55.158;8.CO.55.196; 8.CO.55.223; 8.CO.55.240; 8.CO.55.244; 8.CO.55.243;8.CO.55.247; 8.CO.56.157; 8.CO.56.158; 8.CO.56.196; 8.CO.56.223;8.CO.56.240; 8.CO.56.244; 8.CO.56.243; 8.CO.56.247; 8.CO.157.157;8.CO.157.158; 8.CO.157.196; 8.CO.157.223; 8.CO.157.240; 8.CO.157.244;8.CO.157.243; 8.CO.157.247; 8.CO.196.157; 8.CO.196.158; 8.CO.196.196;8.CO.196.223; 8.CO.196.240; 8.CO.196.244; 8.CO.196.243; 8.CO.196.247;8.CO.223.157; 8.CO.223.158; 8.CO.223.196; 8.CO.223.223; 8.CO.223.240;8.CO.223.244; 8.CO.223.243; 8.CO.223.247; 8.CO.240.157; 8.CO.240.158;8.CO.240.196; 8.CO.240.223; 8.CO.240.240; 8.CO.240.244; 8.CO.240.243;8.CO.240.247; 8.CO.244.157; 8.CO.244.158; 8.CO.244.196; 8.CO.244.223;8.CO.244.240; 8.CO.244.244; 8.CO.244.243; 8.CO.244.247; 8.CO.247.157;8.CO.247.158; 8.CO.247.196; 8.CO.247.223; 8.CO.247.240; 8.CO.247.244;8.CO.247.243; 8.CO.247.247; Prodrugs of 9.AH 9.AH.4.157; 9.AH.4.158;9.AH.4.196; 9.AH.4.223; 9.AH.4.240; 9.AH.4.244; 9.AH.4.243; 9.AH.4.247;9.AH.5.157; 9.AH.5.158; 9.AH.5.196; 9.AH.5.223; 9.AH.5.240; 9.AH.5.244;9.AH.5.243; 9.AH.5.247; 9.AH.7.157; 9.AH.7.158; 9.AH.7.196; 9.AH.7.223;9.AH.7.240; 9.AH.7.244; 9.AH.7.243; 9.AH.7.247; 9.AH.15.157;9.AH.15.158; 9.AH.15.196; 9.AH.15.223; 9.AH.15.240; 9.AH.15.244;9.AH.15.243; 9.AH.15.247; 9.AH.16.157; 9.AH.16.158; 9.AH.16.196;9.AH.16.223; 9.AH.16.240; 9.AH.16.244; 9.AH.16.243; 9.AH.16.247;9.AH.18.157; 9.AH.18.158; 9.AH.18.196; 9.AH.18.223; 9.AH.18.240;9.AH.18.244; 9.AH.18.243; 9.AH.18.247; 9.AH.26.157; 9.AH.26.158;9.AH.26.196; 9.AH.26.223; 9.AH.26.240; 9.AH.26.244; 9.AH.26.243;9.AH.26.247; 9.AH.27.157; 9.AH.27.158; 9.AH.27.196; 9.AH.27.223;9.AH.27.240; 9.AH.27.244; 9.AH.27.243; 9.AH.27.247; 9.AH.29.157;9.AH.29.158; 9.AH.29.196; 9.AH.29.223; 9.AH.29.240; 9.AH.29.244;9.AH.29.243; 9.AH.29.247; 9.AH.54.157; 9.AH.54.158; 9.AH.54.196;9.AH.54.223; 9.AH.54.240; 9.AH.54.244; 9.AH.54.243; 9.AH.54.247;9.AH.55.157; 9.AH.55.158; 9.AH.55.196; 9.AH.55.223; 9.AH.55.240;9.AH.55.244; 9.AH.55.243; 9.AH.55.247; 9.AH.56.157; 9.AH.56.158;9.AH.56.196; 9.AH.56.223; 9.AH.56.240; 9.AH.56.244; 9.AH.56.243;9.AH.56.247; 9.AH.157.157; 9.AH.157.158; 9.AH.157.196; 9.AH.157.223;9.AH.157.240; 9.AH.157.244; 9.AH.157.243; 9.AH.157.247; 9.AH.196.157;9.AH.196.158; 9.AH.196.196; 9.AH.196.223; 9.AH.196.240; 9.AH.196.244;9.AH.196.243; 9.AH.196.247; 9.AH.223.157; 9.AH.223.158; 9.AH.223.196;9.AH.223.223; 9.AH.223.240; 9.AH.223.244; 9.AH.223.243; 9.AH.223.247;9.AH.240.157; 9.AH.240.158; 9.AH.240.196; 9.AH.240.223; 9.AH.240.240;9.AH.240.244; 9.AH.240.243; 9.AH.240.247; 9.AH.244.157; 9.AH.244.158;9.AH.244.196; 9.AH.244.223; 9.AH.244.240; 9.AH.244.244; 9.AH.244.243;9.AH.244.247; 9.AH.247.157; 9.AH.247.158; 9.AH.247.196; 9.AH.247.223;9.AH.247.240; 9.AH.247.244; 9.AH.247.243; 9.AH.247.247; Prodrugs of 9.AJ9.AJ.4.157; 9.AJ.4.158; 9.AJ.4.196; 9.AJ.4.223; 9.AJ.4.240; 9.AJ.4.244;9.AJ.4.243; 9.AJ.4.247; 9.AJ.5.157; 9.AJ.5.158; 9.AJ.5.196; 9.AJ.5.223;9.AJ.5.240; 9.AJ.5.244; 9.AJ.5.243; 9.AJ.5.247; 9.AJ.7.157; 9.AJ.7.158;9.AJ.7.196; 9.AJ.7.223; 9.AJ.7.240; 9.AJ.7.244; 9.AJ.7.243; 9.AJ.7.247;9.AJ.15.157; 9.AJ.15.158; 9.AJ.15.196; 9.AJ.15.223; 9.AJ.15.240;9.AJ.15.244; 9.AJ.15.243; 9.AJ.15.247; 9.AJ.16.157; 9.AJ.16.158;9.AJ.16.196; 9.AJ.16.223; 9.AJ.16.240; 9.AJ.16.244; 9.AJ.16.243;9.AJ.16.247; 9.AJ.18.157; 9.AJ.18.158; 9.AJ.18.196; 9.AJ.18.223;9.AJ.18.240; 9.AJ.18.244; 9.AJ.18.243; 9.AJ.18.247; 9.AJ.26.157;9.AJ.26.158; 9.AJ.26.196; 9.AJ.26.223; 9.AJ.26.240; 9.AJ.26.244;9.AJ.26.243; 9.AJ.26.247; 9.AJ.27.157; 9.AJ.27.158; 9.AJ.27.196;9.AJ.27.223; 9.AJ.27.240; 9.AJ.27.244; 9.AJ.27.243; 9.AJ.27.247;9.AJ.29.157; 9.AJ.29.158; 9.AJ.29.196; 9.AJ.29.223; 9.AJ.29.240;9.AJ.29.244; 9.AJ.29.243; 9.AJ.29.247; 9.AJ.54.157; 9.AJ.54.158;9.AJ.54.196; 9.AJ.54.223; 9.AJ.54.240; 9.AJ.54.244; 9.AJ.54.243;9.AJ.54.247; 9.AJ.55.157; 9.AJ.55.158; 9.AJ.55.196; 9.AJ.55.223;9.AJ.55.240; 9.AJ.55.244; 9.AJ.55.243; 9.AJ.55.247; 9.AJ.56.157;9.AJ.56.158; 9.AJ.56.196; 9.AJ.56.223; 9.AJ.56.240; 9.AJ.56.244;9.AJ.56.243; 9.AJ.56.247; 9.AJ.157.157; 9.AJ.157.158; 9.AJ.157.196;9.AJ.157.223; 9.AJ.157.240; 9.AJ.157.244; 9.AJ.157.243; 9.AJ.157.247;9.AJ.196.157; 9.AJ.196.158; 9.AJ.196.196; 9.AJ.196.223; 9.AJ.196.240;9.AJ.196.244; 9.AJ.196.243; 9.AJ.196.247; 9.AJ.223.157; 9.AJ.223.158;9.AJ.223.196; 9.AJ.223.223; 9.AJ.223.240; 9.AJ.223.244; 9.AJ.223.243;9.AJ.223.247; 9.AJ.240.157; 9.AJ.240.158; 9.AJ.240.196; 9.AJ.240.223;9.AJ.240.240; 9.AJ.240.244; 9.AJ.240.243; 9.AJ.240.247; 9.AJ.244.157;9.AJ.244.158; 9.AJ.244.196; 9.AJ.244.223; 9.AJ.244.240; 9.AJ.244.244;9.AJ.244.243; 9.AJ.244.247; 9.AJ.247.157; 9.AJ.247.158; 9.AJ.247.196;9.AJ.247.223; 9.AJ.247.240; 9.AJ.247.244; 9.AJ.247.243; 9.AJ.247.247;Prodrugs of 9.AN 9.AN.4.157; 9.AN.4.158; 9.AN.4.196; 9.AN.4.223;9.AN.4.240; 9.AN.4.244; 9.AN.4.243; 9.AN.4.247; 9.AN.5.157; 9.AN.5.158;9.AN.5.196; 9.AN.5.223; 9.AN.5.240; 9.AN.5.244; 9.AN.5.243; 9.AN.5.247;9.AN.7.157; 9.AN.7.158; 9.AN.7.196; 9.AN.7.223; 9.AN.7.240; 9.AN.7.244;9.AN.7.243; 9.AN.7.247; 9.AN.15.157; 9.AN.15.158; 9.AN.15.196;9.AN.15.223; 9.AN.15.240; 9.AN.15.244; 9.AN.15.243; 9.AN.15.247;9.AN.16.157; 9.AN.16.158; 9.AN.16.196; 9.AN.16.223; 9.AN.16.240;9.AN.16.244; 9.AN.16.243; 9.AN.16.247; 9.AN.18.157; 9.AN.18.158;9.AN.18.196; 9.AN.18.223; 9.AN.18.240; 9.AN.18.244; 9.AN.18.243;9.AN.18.247; 9.AN.26.157; 9.AN.26.158; 9.AN.26.196; 9.AN.26.223;9.AN.26.240; 9.AN.26.244; 9.AN.26.243; 9.AN.26.247; 9.AN.27.157;9.AN.27.158; 9.AN.27.196; 9.AN.27.223; 9.AN.27.240; 9.AN.27.244;9.AN.27.243; 9.AN.27.247; 9.AN.29.157; 9.AN.29.158; 9.AN.29.196;9.AN.29.223; 9.AN.29.240; 9.AN.29.244; 9.AN.29.243; 9.AN.29.247;9.AN.54.157; 9.AN.54.158; 9.AN.54.196; 9.AN.54.223; 9.AN.54.240;9.AN.54.244; 9.AN.54.243; 9.AN.54.247; 9.AN.55.157; 9.AN.55.158;9.AN.55.196; 9.AN.55.223; 9.AN.55.240; 9.AN.55.244; 9.AN.55.243;9.AN.55.247; 9.AN.56.157; 9.AN.56.158; 9.AN.56.196; 9.AN.56.223;9.AN.56.240; 9.AN.56.244; 9.AN.56.243; 9.AN.56.247; 9.AN.157.157;9.AN.157.158; 9.AN.157.196; 9.AN.157.223; 9.AN.157.240; 9.AN.157.244;9.AN.157.243; 9.AN.157.247; 9.AN.196.157; 9.AN.196.158; 9.AN.196.196;9.AN.196.223; 9.AN.196.240; 9.AN.196.244; 9.AN.196.243; 9.AN.196.247;9.AN.223.157; 9.AN.223.158; 9.AN.223.196; 9.AN.223.223; 9.AN.223.240;9.AN.223.244; 9.AN.223.243; 9.AN.223.247; 9.AN.240.157; 9.AN.240.158;9.AN.240.196; 9.AN.240.223; 9.AN.240.240; 9.AN.240.244; 9.AN.240.243;9.AN.240.247; 9.AN.244.157; 9.AN.244.158; 9.AN.244.196; 9.AN.244.223;9.AN.244.240; 9.AN.244.244; 9.AN.244.243; 9.AN.244.247; 9.AN.247.157;9.AN.247.158; 9.AN.247.196; 9.AN.247.223; 9.AN.247.240; 9.AN.247.244;9.AN.247.243; 9.AN.247.247; Prodrugs of 9.AP 9.AP.4.157; 9.AP.4.158;9.AP.4.196; 9.AP.4.223; 9.AP.4.240; 9.AP.4.244; 9.AP.4.243; 9.AP.4.247;9.AP.5.157; 9.AP.5.158; 9.AP.5.196; 9.AP.5.223; 9.AP.5.240; 9.AP.5.244;9.AP.5.243; 9.AP.5.247; 9.AP.7.157; 9.AP.7.158; 9.AP.7.196; 9.AP.7.223;9.AP.7.240; 9.AP.7.244; 9.AP.7.243; 9.AP.7.247; 9.AP.15.157;9.AP.15.158; 9.AP.15.196; 9.AP.15.223; 9.AP.15.240; 9.AP.15.244;9.AP.15.243; 9.AP.15.247; 9.AP.16.157; 9.AP.16.158; 9.AP.16.196;9.AP.16.223; 9.AP.16.240; 9.AP.16.244; 9.AP.16.243; 9.AP.16.247;9.AP.18.157; 9.AP.18.158; 9.AP.18.196; 9.AP.18.223; 9.AP.18.240;9.AP.18.244; 9.AP.18.243; 9.AP.18.247; 9.AP.26.157; 9.AP.26.158;9.AP.26.196; 9.AP.26.223; 9.AP.26.240; 9.AP.26.244; 9.AP.26.243;9.AP.26.247; 9.AP.27.157; 9.AP.27.158; 9.AP.27.196; 9.AP.27.223;9.AP.27.240; 9.AP.27.244; 9.AP.27.243; 9.AP.27.247; 9.AP.29.157;9.AP.29.158; 9.AP.29.196; 9.AP.29.223; 9.AP.29.240; 9.AP.29.244;9.AP.29.243; 9.AP.29.247; 9.AP.54.157; 9.AP.54.158; 9.AP.54.196;9.AP.54.223; 9.AP.54.240; 9.AP.54.244; 9.AP.54.243; 9.AP.54.247;9.AP.55.157; 9.AP.55.158; 9.AP.55.196; 9.AP.55.223; 9.AP.55.240;9.AP.55.244; 9.AP.55.243; 9.AP.55.247; 9.AP.56.157; 9.AP.56.158;9.AP.56.196; 9.AP.56.223; 9.AP.56.240; 9.AP.56.244; 9.AP.56.243;9.AP.56.247; 9.AP.157.157; 9.AP.157.158; 9.AP.157.196; 9.AP.157.223;9.AP.157.240; 9.AP.157.244; 9.AP.157.243; 9.AP.157.247; 9.AP.196.157;9.AP.196.158; 9.AP.196.196; 9.AP.196.223; 9.AP.196.240; 9.AP.196.244;9.AP.196.243; 9.AP.196.247; 9.AP.223.157; 9.AP.223.158; 9.AP.223.196;9.AP.223.223; 9.AP.223.240; 9.AP.223.244; 9.AP.223.243; 9.AP.223.247;9.AP.240.157; 9.AP.240.158; 9.AP.240.196; 9.AP.240.223; 9.AP.240.240;9.AP.240.244; 9.AP.240.243; 9.AP.240.247; 9.AP.244.157; 9.AP.244.158;9.AP.244.196; 9.AP.244.223; 9.AP.244.240; 9.AP.244.244; 9.AP.244.243;9.AP.244.247; 9.AP.247.157; 9.AP.247.158; 9.AP.247.196; 9.AP.247.223;9.AP.247.240; 9.AP.247.244; 9.AP.247.243; 9.AP.247.247; Prodrugs of 9.AZ9.AZ.4.157; 9.AZ.4.158; 9.AZ.4.196; 9.AZ.4.223; 9.AZ.4.240; 9.AZ.4.244;9.AZ.4.243; 9.AZ.4.247; 9.AZ.5.157; 9.AZ.5.158; 9.AZ.5.196; 9.AZ.5.223;9.AZ.5.240; 9.AZ.5.244; 9.AZ.5.243; 9.AZ.5.247; 9.AZ.7.157; 9.AZ.7.158;9.AZ.7.196; 9.AZ.7.223; 9.AZ.7.240; 9.AZ.7.244; 9.AZ.7.243; 9.AZ.7.247;9.AZ.15.157; 9.AZ.15.158; 9.AZ.15.196; 9.AZ.15.223; 9.AZ.15.240;9.AZ.15.244; 9.AZ.15.243; 9.AZ.15.247; 9.AZ.16.157; 9.AZ.16.158;9.AZ.16.196; 9.AZ.16.223; 9.AZ.16.240; 9.AZ.16.244; 9.AZ.16.243;9.AZ.16.247; 9.AZ.18.157; 9.AZ.18.158; 9.AZ.18.196; 9.AZ.18.223;9.AZ.18.240; 9.AZ.18.244; 9.AZ.18.243; 9.AZ.18.247; 9.AZ.26.157;9.AZ.26.158; 9.AZ.26.196; 9.AZ.26.223; 9.AZ.26.240; 9.AZ.26.244;9.AZ.26.243; 9.AZ.26.247; 9.AZ.27.157; 9.AZ.27.158; 9.AZ.27.196;9.AZ.27.223; 9.AZ.27.240; 9.AZ.27.244; 9.AZ.27.243; 9.AZ.27.247;9.AZ.29.157; 9.AZ.29.158; 9.AZ.29.196; 9.AZ.29.223; 9.AZ.29.240;9.AZ.29.244; 9.AZ.29.243; 9.AZ.29.247; 9.AZ.54.157; 9.AZ.54.158;9.AZ.54.196; 9.AZ.54.223; 9.AZ.54.240; 9.AZ.54.244; 9.AZ.54.243;9.AZ.54.247; 9.AZ.55.157; 9.AZ.55.158; 9.AZ.55.196; 9.AZ.55.223;9.AZ.55.240; 9.AZ.55.244; 9.AZ.55.243; 9.AZ.55.247; 9.AZ.56.157;9.AZ.56.158; 9.AZ.56.196; 9.AZ.56.223; 9.AZ.56.240; 9.AZ.56.244;9.AZ.56.243; 9.AZ.56.247; 9.AZ.157.157; 9.AZ.157.158; 9.AZ.157.196;9.AZ.157.223; 9.AZ.157.240; 9.AZ.157.244; 9.AZ.157.243; 9.AZ.157.247;9.AZ.196.157; 9.AZ.196.158; 9.AZ.196.196; 9.AZ.196.223; 9.AZ.196.240;9.AZ.196.244; 9.AZ.196.243; 9.AZ.196.247; 9.AZ.223.157; 9.AZ.223.158;9.AZ.223.196; 9.AZ.223.223; 9.AZ.223.240; 9.AZ.223.244; 9.AZ.223.243;9.AZ.223.247; 9.AZ.240.157; 9.AZ.240.158; 9.AZ.240.196; 9.AZ.240.223;9.AZ.240.240; 9.AZ.240.244; 9.AZ.240.243; 9.AZ.240.247; 9.AZ.244.157;9.AZ.244.158; 9.AZ.244.196; 9.AZ.244.223; 9.AZ.244.240; 9.AZ.244.244;9.AZ.244.243; 9.AZ.244.247; 9.AZ.247.157; 9.AZ.247.158; 9.AZ.247.196;9.AZ.247.223; 9.AZ.247.240; 9.AZ.247.244; 9.AZ.247.243; 9.AZ.247.247;Prodrugs of 9.BF 9.BF.4.157; 9.BF.4.158; 9.BF.4.196; 9.BF.4.223;9.BF.4.240; 9.BF.4.244; 9.BF.4.243; 9.BF.4.247; 9.BF.5.157; 9.BF.5.158;9.BF.5.196; 9.BF.5.223; 9.BF.5.240; 9.BF.5.244; 9.BF.5.243; 9.BF.5.247;9.BF.7.157; 9.BF.7.158; 9.BF.7.196; 9.BF.7.223; 9.BF.7.240; 9.BF.7.244;9.BF.7.243; 9.BF.7.247; 9.BF.15.157; 9.BF.15.158; 9.BF.15.196;9.BF.15.223; 9.BF.15.240; 9.BF.15.244; 9.BF.15.243; 9.BF.15.247;9.BF.16.157; 9.BF.16.158; 9.BF.16.196; 9.BF.16.223; 9.BF.16.240;9.BF.16.244; 9.BF.16.243; 9.BF.16.247; 9.BF.18.157; 9.BF.18.158;9.BF.18.196; 9.BF.18.223; 9.BF.18.240; 9.BF.18.244; 9.BF.18.243;9.BF.18.247; 9.BF.26.157; 9.BF.26.158; 9.BF.26.196; 9.BF.26.223;9.BF.26.240; 9.BF.26.244; 9.BF.26.243; 9.BF.26.247; 9.BF.27.157;9.BF.27.158; 9.BF.27.196; 9.BF.27.223; 9.BF.27.240; 9.BF.27.244;9.BF.27.243; 9.BF.27.247; 9.BF.29.157; 9.BF.29.158; 9.BF.29.196;9.BF.29.223; 9.BF.29.240; 9.BF.29.244; 9.BF.29.243; 9.BF.29.247;9.BF.54.157; 9.BF.54.158; 9.BF.54.196; 9.BF.54.223; 9.BF.54.240;9.BF.54.244; 9.BF.54.243; 9.BF.54.247; 9.BF.55.157; 9.BF.55.158;9.BF.55.196; 9.BF.55.223; 9.BF.55.240; 9.BF.55.244; 9.BF.55.243;9.BF.55.247; 9.BF.56.157; 9.BF.56.158; 9.BF.56.196; 9.BF.56.223;9.BF.56.240; 9.BF.56.244; 9.BF.56.243; 9.BF.56.247; 9.BF.157.157;9.BF.157.158; 9.BF.157.196; 9.BF.157.223; 9.BF.157.240; 9.BF.157.244;9.BF.157.243; 9.BF.157.247; 9.BF.196.157; 9.BF.196.158; 9.BF.196.196;9.BF.196.223; 9.BF.196.240; 9.BF.196.244; 9.BF.196.243; 9.BF.196.247;9.BF.223.157; 9.BF.223.158; 9.BF.223.196; 9.BF.223.223; 9.BF.223.240;9.BF.223.244; 9.BF.223.243; 9.BF.223.247; 9.BF.240.157; 9.BF.240.158;9.BF.240.196; 9.BF.240.223; 9.BF.240.240; 9.BF.240.244; 9.BF.240.243;9.BF.240.247; 9.BF.244.157; 9.BF.244.158; 9.BF.244.196; 9.BF.244.223;9.BF.244.240; 9.BF.244.244; 9.BF.244.243; 9.BF.244.247; 9.BF.247.157;9.BF.247.158; 9.BF.247.196; 9.BF.247.223; 9.BF.247.240; 9.BF.247.244;9.BF.247.243; 9.BF.247.247; Prodrugs of 9.CI 9.CI.4.157; 9.CI.4.158;9.CI.4.196; 9.CI.4.223; 9.CI.4.240; 9.CI.4.244; 9.CI.4.243; 9.CI.4.247;9.CI.5.157; 9.CI.5.158; 9.CI.5.196; 9.CI.5.223; 9.CI.5.240; 9.CI.5.244;9.CI.5.243; 9.CI.5.247; 9.CI.7.157; 9.CI.7.158; 9.CI.7.196; 9.CI.7.223;9.CI.7.240; 9.CI.7.244; 9.CI.7.243; 9.CI.7.247; 9.CI.15.157;9.CI.15.158; 9.CI.15.196; 9.CI.15.223; 9.CI.15.240; 9.CI.15.244;9.CI.15.243; 9.CI.15.247; 9.CI.16.157; 9.CI.16.158; 9.CI.16.196;9.CI.16.223; 9.CI.16.240; 9.CI.16.244; 9.CI.16.243; 9.CI.16.247;9.CI.18.157; 9.CI.18.158; 9.CI.18.196; 9.CI.18.223; 9.CI.18.240;9.CI.18.244; 9.CI.18.243; 9.CI.18.247; 9.CI.26.157; 9.CI.26.158;9.CI.26.196; 9.CI.26.223; 9.CI.26.240; 9.CI.26.244; 9.CI.26.243;9.CI.26.247; 9.CI.27.157; 9.CI.27.158; 9.CI.27.196; 9.CI.27.223;9.CI.27.240; 9.CI.27.244; 9.CI.27.243; 9.CI.27.247; 9.CI.29.157;9.CI.29.158; 9.CI.29.196; 9.CI.29.223; 9.CI.29.240; 9.CI.29.244;9.CI.29.243; 9.CI.29.247; 9.CI.54.157; 9.CI.54.158; 9.CI.54.196;9.CI.54.223; 9.CI.54.240; 9.CI.54.244; 9.CI.54.243; 9.CI.54.247;9.CI.55.157; 9.CI.55.158; 9.CI.55.196; 9.CI.55.223; 9.CI.55.240;9.CI.55.244; 9.CI.55.243; 9.CI.55.247; 9.CI.56.157; 9.CI.56.158;9.CI.56.196; 9.CI.56.223; 9.CI.56.240; 9.CI.56.244; 9.CI.56.243;9.CI.56.247; 9.CI.157.157; 9.CI.157.158; 9.CI.157.196; 9.CI.157.223;9.CI.157.240; 9.CI.157.244; 9.CI.157.243; 9.CI.157.247; 9.CI.196.157;9.CI.196.158; 9.CI.196.196; 9.CI.196.223; 9.CI.196.240; 9.CI.196.244;9.CI.196.243; 9.CI.196.247; 9.CI.223.157; 9.CI.223.158; 9.CI.223.196;9.CI.223.223; 9.CI.223.240; 9.CI.223.244; 9.CI.223.243; 9.CI.223.247;9.CI.240.157; 9.CI.240.158; 9.CI.240.196; 9.CI.240.223; 9.CI.240.240;9.CI.240.244; 9.CI.240.243; 9.CI.240.247; 9.CI.244.157; 9.CI.244.158;9.CI.244.196; 9.CI.244.223; 9.CI.244.240; 9.CI.244.244; 9.CI.244.243;9.CI.244.247; 9.CI.247.157; 9.CI.247.158; 9.CI.247.196; 9.CI.247.223;9.CI.247.240; 9.CI.247.244; 9.CI.247.243; 9.CI.247.247; Prodrugs of 9.CO9.CO.4.157; 9.CO.4.158; 9.CO.4.196; 9.CO.4.223; 9.CO.4.240; 9.CO.4.244;9.CO.4.243; 9.CO.4.247; 9.CO.5.157; 9.CO.5.158; 9.CO.5.196; 9.CO.5.223;9.CO.5.240; 9.CO.5.244; 9.CO.5.243; 9.CO.5.247; 9.CO.7.157; 9.CO.7.158;9.CO.7.196; 9.CO.7.223; 9.CO.7.240; 9.CO.7.244; 9.CO.7.243; 9.CO.7.247;9.CO.15.157; 9.CO.15.158; 9.CO.15.196; 9.CO.15.223; 9.CO.15.240;9.CO.15.244; 9.CO.15.243; 9.CO.15.247; 9.CO.16.157; 9.CO.16.158;9.CO.16.196; 9.CO.16.223; 9.CO.16.240; 9.CO.16.244; 9.CO.16.243;9.CO.16.247; 9.CO.18.157; 9.CO.18.158; 9.CO.18.196; 9.CO.18.223;9.CO.18.240; 9.CO.18.244; 9.CO.18.243; 9.CO.18.247; 9.CO.26.157;9.CO.26.158; 9.CO.26.196; 9.CO.26.223; 9.CO.26.240; 9.CO.26.244;9.CO.26.243; 9.CO.26.247; 9.CO.27.157; 9.CO.27.158; 9.CO.27.196;9.CO.27.223; 9.CO.27.240; 9.CO.27.244; 9.CO.27.243; 9.CO.27.247;9.CO.29.157; 9.CO.29.158; 9.CO.29.196; 9.CO.29.223; 9.CO.29.240;9.CO.29.244; 9.CO.29.243; 9.CO.29.247; 9.CO.54.157; 9.CO.54.158;9.CO.54.196; 9.CO.54.223; 9.CO.54.240; 9.CO.54.244; 9.CO.54.243;9.CO.54.247; 9.CO.55.157; 9.CO.55.158; 9.CO.55.196; 9.CO.55.223;9.CO.55.240; 9.CO.55.244; 9.CO.55.243; 9.CO.55.247; 9.CO.56.157;9.CO.56.158; 9.CO.56.196; 9.CO.56.223; 9.CO.56.240; 9.CO.56.244;9.CO.56.243; 9.CO.56.247; 9.CO.157.157; 9.CO.157.158; 9.CO.157.196;9.CO.157.223; 9.CO.157.240; 9.CO.157.244; 9.CO.157.243; 9.CO.157.247;9.CO.196.157; 9.CO.196.158; 9.CO.196.196; 9.CO.196.223; 9.CO.196.240;9.CO.196.244; 9.CO.196.243; 9.CO.196.247; 9.CO.223.157; 9.CO.223.158;9.CO.223.196; 9.CO.223.223; 9.CO.223.240; 9.CO.223.244; 9.CO.223.243;9.CO.223.247; 9.CO.240.157; 9.CO.240.158; 9.CO.240.196; 9.CO.240.223;9.CO.240.240; 9.CO.240.244; 9.CO.240.243; 9.CO.240.247; 9.CO.244.157;9.CO.244.158; 9.CO.244.196; 9.CO.244.223; 9.CO.244.240; 9.CO.244.244;9.CO.244.243; 9.CO.244.247; 9.CO.247.157; 9.CO.247.158; 9.CO.247.196;9.CO.247.223; 9.CO.247.240; 9.CO.247.244; 9.CO.247.243; 9.CO.247.247;Prodrugs of 10.AH 10.AH.4.157; 10.AH.4.158; 10.AH.4.196; 10.AH.4.223;10.AH.4.240; 10.AH.4.244; 10.AH.4.243; 10.AH.4.247; 10.AH.5.157;10.AH.5.158; 10.AH.5.196; 10.AH.5.223; 10.AH.5.240; 10.AH.5.244;10.AH.5.243; 10.AH.5.247; 10.AH.7.157; 10.AH.7.158; 10.AH.7.196;10.AH.7.223; 10.AH.7.240; 10.AH.7.244; 10.AH.7.243; 10.AH.7.247;10.AH.15.157; 10.AH.15.158; 10.AH.15.196; 10.AH.15.223; 10.AH.15.240;10.AH.15.244; 10.AH.15.243; 10.AH.15.247; 10.AH.16.157; 10.AH.16.158;10.AH.16.196; 10.AH.16.223; 10.AH.16.240; 10.AH.16.244; 10.AH.16.243;10.AH.16.247; 10.AH.18.157; 10.AH.18.158; 10.AH.18.196; 10.AH.18.223;10.AH.18.240; 10.AH.18.244; 10.AH.18.243; 10.AH.18.247; 10.AH.26.157;10.AH.26.158; 10.AH.26.196; 10.AH.26.223; 10.AH.26.240; 10.AH.26.244;10.AH.26.243; 10.AH.26.247; 10.AH.27.157; 10.AH.27.158; 10.AH.27.196;10.AH.27.223; 10.AH.27.240; 10.AH.27.244; 10.AH.27.243; 10.AH.27.247;10.AH.29.157; 10.AH.29.158; 10.AH.29.196; 10.AH.29.223; 10.AH.29.240;10.AH.29.244; 10.AH.29.243; 10.AH.29.247; 10.AH.54.157; 10.AH.54.158;10.AH.54.196; 10.AH.54.223; 10.AH.54.240; 10.AH.54.244; 10.AH.54.243;10.AH.54.247; 10.AH.55.157; 10.AH.55.158; 10.AH.55.196; 10.AH.55.223;10.AH.55.240; 10.AH.55.244; 10.AH.55.243; 10.AH.55.247; 10.AH.56.157;10.AH.56.158; 10.AH.56.196; 10.AH.56.223; 10.AH.56.240; 10.AH.56.244;10.AH.56.243; 10.AH.56.247; 10.AH.157.157; 10.AH.157.158; 10.AH.157.196;10.AH.157.223; 10.AH.157.240; 10.AH.157.244; 10.AH.157.243;10.AH.157.247; 10.AH.196.157; 10.AH.196.158; 10.AH.196.196;10.AH.196.223; 10.AH.196.240; 10.AH.196.244; 10.AH.196.243;10.AH.196.247; 10.AH.223.157; 10.AH.223.158; 10.AH.223.196;10.AH.223.223; 10.AH.223.240; 10.AH.223.244; 10.AH.223.243;10.AH.223.247; 10.AH.240.157; 10.AH.240.158; 10.AH.240.196;10.AH.240.223; 10.AH.240.240; 10.AH.240.244; 10.AH.240.243;10.AH.240.247; 10.AH.244.157; 10.AH.244.158; 10.AH.244.196;10.AH.244.223; 10.AH.244.240; 10.AH.244.244; 10.AH.244.243;10.AH.244.247; 10.AH.247.157; 10.AH.247.158; 10.AH.247.196;10.AH.247.223; 10.AH.247.240; 10.AH.247.244; 10.AH.247.243;10.AH.247.247; Prodrugs of 10.AJ 10.AJ.4.157; 10.AJ.4.158; 10.AJ.4.196;10.AJ.4.223; 10.AJ.4.240; 10.AJ.4.244; 10.AJ.4.243; 10.AJ.4.247;10.AJ.5.157; 10.AJ.5.158; 10.AJ.5.196; 10.AJ.5.223; 10.AJ.5.240;10.AJ.5.244; 10.AJ.5.243; 10.AJ.5.247; 10.AJ.7.157; 10.AJ.7.158;10.AJ.7.196; 10.AJ.7.223; 10.AJ.7.240; 10.AJ.7.244; 10.AJ.7.243;10.AJ.7.247; 10.AJ.15.157; 10.AJ.15.158; 10.AJ.15.196; 10.AJ.15.223;10.AJ.15.240; 10.AJ.15.244; 10.AJ.15.243; 10.AJ.15.247; 10.AJ.16.157;10.AJ.16.158; 10.AJ.16.196; 10.AJ.16.223; 10.AJ.16.240; 10.AJ.16.244;10.AJ.16.243; 10.AJ.16.247; 10.AJ.18.157; 10.AJ.18.158; 10.AJ.18.196;10.AJ.18.223; 10.AJ.18.240; 10.AJ.18.244; 10.AJ.18.243; 10.AJ.18.247;10.AJ.26.157; 10.AJ.26.158; 10.AJ.26.196; 10.AJ.26.223; 10.AJ.26.240;10.AJ.26.244; 10.AJ.26.243; 10.AJ.26.247; 10.AJ.27.157; 10.AJ.27.158;10.AJ.27.196; 10.AJ.27.223; 10.AJ.27.240; 10.AJ.27.244; 10.AJ.27.243;10.AJ.27.247; 10.AJ.29.157; 10.AJ.29.158; 10.AJ.29.196; 10.AJ.29.223;10.AJ.29.240; 10.AJ.29.244; 10.AJ.29.243; 10.AJ.29.247; 10.AJ.54.157;10.AJ.54.158; 10.AJ.54.196; 10.AJ.54.223; 10.AJ.54.240; 10.AJ.54.244;10.AJ.54.243; 10.AJ.54.247; 10.AJ.55.157; 10.AJ.55.158; 10.AJ.55.196;10.AJ.55.223; 10.AJ.55.240; 10.AJ.55.244; 10.AJ.55.243; 10.AJ.55.247;10.AJ.56.157; 10.AJ.56.158; 10.AJ.56.196; 10.AJ.56.223; 10.AJ.56.240;10.AJ.56.244; 10.AJ.56.243; 10.AJ.56.247; 10.AJ.157.157; 10.AJ.157.158;10.AJ.157.196; 10.AJ.157.223; 10.AJ.157.240; 10.AJ.157.244;10.AJ.157.243; 10.AJ.157.247; 10.AJ.196.157; 10.AJ.196.158;10.AJ.196.196; 10.AJ.196.223; 10.AJ.196.240; 10.AJ.196.244;10.AJ.196.243; 10.AJ.196.247; 10.AJ.223.157; 10.AJ.223.158;10.AJ.223.196; 10.AJ.223.223; 10.AJ.223.240; 10.AJ.223.244;10.AJ.223.243; 10.AJ.223.247; 10.AJ.240.157; 10.AJ.240.158;10.AJ.240.196; 10.AJ.240.223; 10.AJ.240.240; 10.AJ.240.244;10.AJ.240.243; 10.AJ.240.247; 10.AJ.244.157; 10.AJ.244.158;10.AJ.244.196; 10.AJ.244.223; 10.AJ.244.240; 10.AJ.244.244;10.AJ.244.243; 10.AJ.244.247; 10.AJ.247.157; 10.AJ.247.158;10.AJ.247.196; 10.AJ.247.223; 10.AJ.247.240; 10.AJ.247.244;10.AJ.247.243; 10.AJ.247.247; Prodrugs of 10.AN 10.AN.4.157;10.AN.4.158; 10.AN.4.196; 10.AN.4.223; 10.AN.4.240; 10.AN.4.244;10.AN.4.243; 10.AN.4.247; 10.AN.5.157; 10.AN.5.158; 10.AN.5.196;10.AN.5.223; 10.AN.5.240; 10.AN.5.244; 10.AN.5.243; 10.AN.5.247;10.AN.7.157; 10.AN.7.158; 10.AN.7.196; 10.AN.7.223; 10.AN.7.240;10.AN.7.244; 10.AN.7.243; 10.AN.7.247; 10.AN.15.157; 10.AN.15.158;10.AN.15.196; 10.AN.15.223; 10.AN.15.240; 10.AN.15.244; 10.AN.15.243;10.AN.15.247; 10.AN.16.157; 10.AN.16.158; 10.AN.16.196; 10.AN.16.223;10.AN.16.240; 10.AN.16.244; 10.AN.16.243; 10.AN.16.247; 10.AN.18.157;10.AN.18.158; 10.AN.18.196; 10.AN.18.223; 10.AN.18.240; 10.AN.18.244;10.AN.18.243; 10.AN.18.247; 10.AN.26.157; 10.AN.26.158; 10.AN.26.196;10.AN.26.223; 10.AN.26.240; 10.AN.26.244; 10.AN.26.243; 10.AN.26.247;10.AN.27.157; 10.AN.27.158; 10.AN.27.196; 10.AN.27.223; 10.AN.27.240;10.AN.27.244; 10.AN.27.243; 10.AN.27.247; 10.AN.29.157; 10.AN.29.158;10.AN.29.196; 10.AN.29.223; 10.AN.29.240; 10.AN.29.244; 10.AN.29.243;10.AN.29.247; 10.AN.54.157; 10.AN.54.158; 10.AN.54.196; 10.AN.54.223;10.AN.54.240; 10.AN.54.244; 10.AN.54.243; 10.AN.54.247; 10.AN.55.157;10.AN.55.158; 10.AN.55.196; 10.AN.55.223; 10.AN.55.240; 10.AN.55.244;10.AN.55.243; 10.AN.55.247; 10.AN.56.157; 10.AN.56.158; 10.AN.56.196;10.AN.56.223; 10.AN.56.240; 10.AN.56.244; 10.AN.56.243; 10.AN.56.247;10.AN.157.157; 10.AN.157.158; 10.AN.157.196; 10.AN.157.223;10.AN.157.240; 10.AN.157.244; 10.AN.157.243; 10.AN.157.247;10.AN.196.157; 10.AN.196.158; 10.AN.196.196; 10.AN.196.223;10.AN.196.240; 10.AN.196.244; 10.AN.196.243; 10.AN.196.247;10.AN.223.157; 10.AN.223.158; 10.AN.223.196; 10.AN.223.223;10.AN.223.240; 10.AN.223.244; 10.AN.223.243; 10.AN.223.247;10.AN.240.157; 10.AN.240.158; 10.AN.240.196; 10.AN.240.223;10.AN.240.240; 10.AN.240.244; 10.AN.240.243; 10.AN.240.247;10.AN.244.157; 10.AN.244.158; 10.AN.244.196; 10.AN.244.223;10.AN.244.240; 10.AN.244.244; 10.AN.244.243; 10.AN.244.247;10.AN.247.157; 10.AN.247.158; 10.AN.247.196; 10.AN.247.223;10.AN.247.240; 10.AN.247.244; 10.AN.247.243; 10.AN.247.247; Prodrugs of10.AP 10.AP.4.157; 10.AP.4.158; 10.AP.4.196; 10.AP.4.223; 10.AP.4.240;10.AP.4.244; 10.AP.4.243; 10.AP.4.247; 10.AP.5.157; 10.AP.5.158;10.AP.5.196; 10.AP.5.223; 10.AP.5.240; 10.AP.5.244; 10.AP.5.243;10.AP.5.247; 10.AP.7.157; 10.AP.7.158; 10.AP.7.196; 10.AP.7.223;10.AP.7.240; 10.AP.7.244; 10.AP.7.243; 10.AP.7.247; 10.AP.15.157;10.AP.15.158; 10.AP.15.196; 10.AP.15.223; 10.AP.15.240; 10.AP.15.244;10.AP.15.243; 10.AP.15.247; 10.AP.16.157; 10.AP.16.158; 10.AP.16.196;10.AP.16.223; 10.AP.16.240; 10.AP.16.244; 10.AP.16.243; 10.AP.16.247;10.AP.18.157; 10.AP.18.158; 10.AP.18.196; 10.AP.18.223; 10.AP.18.240;10.AP.18.244; 10.AP.18.243; 10.AP.18.247; 10.AP.26.157; 10.AP.26.158;10.AP.26.196; 10.AP.26.223; 10.AP.26.240; 10.AP.26.244; 10.AP.26.243;10.AP.26.247; 10.AP.27.157; 10.AP.27.158; 10.AP.27.196; 10.AP.27.223;10.AP.27.240; 10.AP.27.244; 10.AP.27.243; 10.AP.27.247; 10.AP.29.157;10.AP.29.158; 10.AP.29.196; 10.AP.29.223; 10.AP.29.240; 10.AP.29.244;10.AP.29.243; 10.AP.29.247; 10.AP.54.157; 10.AP.54.158; 10.AP.54.196;10.AP.54.223; 10.AP.54.240; 10.AP.54.244; 10.AP.54.243; 10.AP.54.247;10.AP.55.157; 10.AP.55.158; 10.AP.55.196; 10.AP.55.223; 10.AP.55.240;10.AP.55.244; 10.AP.55.243; 10.AP.55.247; 10.AP.56.157; 10.AP.56.158;10.AP.56.196; 10.AP.56.223; 10.AP.56.240; 10.AP.56.244; 10.AP.56.243;10.AP.56.247; 10.AP.157.157; 10.AP.157.158; 10.AP.157.196;10.AP.157.223; 10.AP.157.240; 10.AP.157.244; 10.AP.157.243;10.AP.157.247; 10.AP.196.157; 10.AP.196.158; 10.AP.196.196;10.AP.196.223; 10.AP.196.240; 10.AP.196.244; 10.AP.196.243;10.AP.196.247; 10.AP.223.157; 10.AP.223.158; 10.AP.223.196;10.AP.223.223; 10.AP.223.240; 10.AP.223.244; 10.AP.223.243;10.AP.223.247; 10.AP.240.157; 10.AP.240.158; 10.AP.240.196;10.AP.240.223; 10.AP.240.240; 10.AP.240.244; 10.AP.240.243;10.AP.240.247; 10.AP.244.157; 10.AP.244.158; 10.AP.244.196;10.AP.244.223; 10.AP.244.240; 10.AP.244.244; 10.AP.244.243;10.AP.244.247; 10.AP.247.157; 10.AP.247.158; 10.AP.247.196;10.AP.247.223; 10.AP.247.240; 10.AP.247.244; 10.AP.247.243;10.AP.247.247; Prodrugs of 10.AZ 10.AZ.4.157; 10.AZ.4.158; 10.AZ.4.196;10.AZ.4.223; 10.AZ.4.240; 10.AZ.4.244; 10.AZ.4.243; 10.AZ.4.247;10.AZ.5.157; 10.AZ.5.158; 10.AZ.5.196; 10.AZ.5.223; 10.AZ.5.240;10.AZ.5.244; 10.AZ.5.243; 10.AZ.5.247; 10.AZ.7.157; 10.AZ.7.158;10.AZ.7.196; 10.AZ.7.223; 10.AZ.7.240; 10.AZ.7.244; 10.AZ.7.243;10.AZ.7.247; 10.AZ.15.157; 10.AZ.15.158; 10.AZ.15.196; 10.AZ.15.223;10.AZ.15.240; 10.AZ.15.244; 10.AZ.15.243; 10.AZ.15.247; 10.AZ.16.157;10.AZ.16.158; 10.AZ.16.196; 10.AZ.16.223; 10.AZ.16.240; 10.AZ.16.244;10.AZ.16.243; 10.AZ.16.247; 10.AZ.18.157; 10.AZ.18.158; 10.AZ.18.196;10.AZ.18.223; 10.AZ.18.240; 10.AZ.18.244; 10.AZ.18.243; 10.AZ.18.247;10.AZ.26.157; 10.AZ.26.158; 10.AZ.26.196; 10.AZ.26.223; 10.AZ.26.240;10.AZ.26.244; 10.AZ.26.243; 10.AZ.26.247; 10.AZ.27.157; 10.AZ.27.158;10.AZ.27.196; 10.AZ.27.223; 10.AZ.27.240; 10.AZ.27.244; 10.AZ.27.243;10.AZ.27.247; 10.AZ.29.157; 10.AZ.29.158; 10.AZ.29.196; 10.AZ.29.223;10.AZ.29.240; 10.AZ.29.244; 10.AZ.29.243; 10.AZ.29.247; 10.AZ.54.157;10.AZ.54.158; 10.AZ.54.196; 10.AZ.54.223; 10.AZ.54.240; 10.AZ.54.244;10.AZ.54.243; 10.AZ.54.247; 10.AZ.55.157; 10.AZ.55.158; 10.AZ.55.196;10.AZ.55.223; 10.AZ.55.240; 10.AZ.55.244; 10.AZ.55.243; 10.AZ.55.247;10.AZ.56.157; 10.AZ.56.158; 10.AZ.56.196; 10.AZ.56.223; 10.AZ.56.240;10.AZ.56.244; 10.AZ.56.243; 10.AZ.56.247; 10.AZ.157.157; 10.AZ.157.158;10.AZ.157.196; 10.AZ.157.223; 10.AZ.157.240; 10.AZ.157.244;10.AZ.157.243; 10.AZ.157.247; 10.AZ.196.157; 10.AZ.196.158;10.AZ.196.196; 10.AZ.196.223; 10.AZ.196.240; 10.AZ.196.244;10.AZ.196.243; 10.AZ.196.247; 10.AZ.223.157; 10.AZ.223.158;10.AZ.223.196; 10.AZ.223.223; 10.AZ.223.240; 10.AZ.223.244;10.AZ.223.243; 10.AZ.223.247; 10.AZ.240.157; 10.AZ.240.158;10.AZ.240.196; 10.AZ.240.223; 10.AZ.240.240; 10.AZ.240.244;10.AZ.240.243; 10.AZ.240.247; 10.AZ.244.157; 10.AZ.244.158;10.AZ.244.196; 10.AZ.244.223; 10.AZ.244.240; 10.AZ.244.244;10.AZ.244.243; 10.AZ.244.247; 10.AZ.247.157; 10.AZ.247.158;10.AZ.247.196; 10.AZ.247.223; 10.AZ.247.240; 10.AZ.247.244;10.AZ.247.243; 10.AZ.247.247; Prodrugs of 10.BF 10.BF.4.157;10.BF.4.158; 10.BF.4.196; 10.BF.4.223; 10.BF.4.240; 10.BF.4.244;10.BF.4.243; 10.BF.4.247; 10.BF.5.157; 10.BF.5.158; 10.BF.5.196;10.BF.5.223; 10.BF.5.240; 10.BF.5.244; 10.BF.5.243; 10.BF.5.247;10.BF.7.157; 10.BF.7.158; 10.BF.7.196; 10.BF.7.223; 10.BF.7.240;10.BF.7.244; 10.BF.7.243; 10.BF.7.247; 10.BF.15.157; 10.BF.15.158;10.BF.15.196; 10.BF.15.223; 10.BF.15.240; 10.BF.15.244; 10.BF.15.243;10.BF.15.247; 10.BF.16.157; 10.BF.16.158; 10.BF.16.196; 10.BF.16.223;10.BF.16.240; 10.BF.16.244; 10.BF.16.243; 10.BF.16.247; 10.BF.18.157;10.BF.18.158; 10.BF.18.196; 10.BF.18.223; 10.BF.18.240; 10.BF.18.244;10.BF.18.243; 10.BF.18.247; 10.BF.26.157; 10.BF.26.158; 10.BF.26.196;10.BF.26.223; 10.BF.26.240; 10.BF.26.244; 10.BF.26.243; 10.BF.26.247;10.BF.27.157; 10.BF.27.158; 10.BF.27.196; 10.BF.27.223; 10.BF.27.240;10.BF.27.244; 10.BF.27.243; 10.BF.27.247; 10.BF.29.157; 10.BF.29.158;10.BF.29.196; 10.BF.29.223; 10.BF.29.240; 10.BF.29.244; 10.BF.29.243;10.BF.29.247; 10.BF.54.157; 10.BF.54.158; 10.BF.54.196; 10.BF.54.223;10.BF.54.240; 10.BF.54.244; 10.BF.54.243; 10.BF.54.247; 10.BF.55.157;10.BF.55.158; 10.BF.55.196; 10.BF.55.223; 10.BF.55.240; 10.BF.55.244;10.BF.55.243; 10.BF.55.247; 10.BF.56.157; 10.BF.56.158; 10.BF.56.196;10.BF.56.223; 10.BF.56.240; 10.BF.56.244; 10.BF.56.243; 10.BF.56.247;10.BF.157.157; 10.BF.157.158; 10.BF.157.196; 10.BF.157.223;10.BF.157.240; 10.BF.157.244; 10.BF.157.243; 10.BF.157.247;10.BF.196.157; 10.BF.196.158; 10.BF.196.196; 10.BF.196.223;10.BF.196.240; 10.BF.196.244; 10.BF.196.243; 10.BF.196.247;10.BF.223.157; 10.BF.223.158; 10.BF.223.196; 10.BF.223.223;10.BF.223.240; 10.BF.223.244; 10.BF.223.243; 10.BF.223.247;10.BF.240.157; 10.BF.240.158; 10.BF.240.196; 10.BF.240.223;10.BF.240.240; 10.BF.240.244; 10.BF.240.243; 10.BF.240.247;10.BF.244.157; 10.BF.244.158; 10.BF.244.196; 10.BF.244.223;10.BF.244.240; 10.BF.244.244; 10.BF.244.243; 10.BF.244.247;10.BF.247.157; 10.BF.247.158; 10.BF.247.196; 10.BF.247.223;10.BF.247.240; 10.BF.247.244; 10.BF.247.243; 10.BF.247.247; Prodrugs of10.CI 10.CI.4.157; 10.CI.4.158; 10.CI.4.196; 10.CI.4.223; 10.CI.4.240;10.CI.4.244; 10.CI.4.243; 10.CI.4.247; 10.CI.5.157; 10.CI.5.158;10.CI.5.196; 10.CI.5.223; 10.CI.5.240; 10.CI.5.244; 10.CI.5.243;10.CI.5.247; 10.CI.7.157; 10.CI.7.158; 10.CI.7.196; 10.CI.7.223;10.CI.7.240; 10.CI.7.244; 10.CI.7.243; 10.CI.7.247; 10.CI.15.157;10.CI.15.158; 10.CI.15.196; 10.CI.15.223; 10.CI.15.240; 10.CI.15.244;10.CI.15.243; 10.CI.15.247; 10.CI.16.157; 10.CI.16.158; 10.CI.16.196;10.CI.16.223; 10.CI.16.240; 10.CI.16.244; 10.CI.16.243; 10.CI.16.247;10.CI.18.157; 10.CI.18.158; 10.CI.18.196; 10.CI.18.223; 10.CI.18.240;10.CI.18.244; 10.CI.18.243; 10.CI.18.247; 10.CI.26.157; 10.CI.26.158;10.CI.26.196; 10.CI.26.223; 10.CI.26.240; 10.CI.26.244; 10.CI.26.243;10.CI.26.247; 10.CI.27.157; 10.CI.27.158; 10.CI.27.196; 10.CI.27.223;10.CI.27.240; 10.CI.27.244; 10.CI.27.243; 10.CI.27.247; 10.CI.29.157;10.CI.29.158; 10.CI.29.196; 10.CI.29.223; 10.CI.29.240; 10.CI.29.244;10.CI.29.243; 10.CI.29.247; 10.CI.54.157; 10.CI.54.158; 10.CI.54.196;10.CI.54.223; 10.CI.54.240; 10.CI.54.244; 10.CI.54.243; 10.CI.54.247;10.CI.55.157; 10.CI.55.158; 10.CI.55.196; 10.CI.55.223; 10.CI.55.240;10.CI.55.244; 10.CI.55.243; 10.CI.55.247; 10.CI.56.157; 10.CI.56.158;10.CI.56.196; 10.CI.56.223; 10.CI.56.240; 10.CI.56.244; 10.CI.56.243;10.CI.56.247; 10.CI.157.157; 10.CI.157.158; 10.CI.157.196;10.CI.157.223; 10.CI.157.240; 10.CI.157.244; 10.CI.157.243;10.CI.157.247; 10.CI.196.157; 10.CI.196.158; 10.CI.196.196;10.CI.196.223; 10.CI.196.240; 10.CI.196.244; 10.CI.196.243;10.CI.196.247; 10.CI.223.157; 10.CI.223.158; 10.CI.223.196;10.CI.223.223; 10.CI.223.240; 10.CI.223.244; 10.CI.223.243;10.CI.223.247; 10.CI.240.157; 10.CI.240.158; 10.CI.240.196;10.CI.240.223; 10.CI.240.240; 10.CI.240.244; 10.CI.240.243;10.CI.240.247; 10.CI.244.157; 10.CI.244.158; 10.CI.244.196;10.CI.244.223; 10.CI.244.240; 10.CI.244.244; 10.CI.244.243;10.CI.244.247; 10.CI.247.157; 10.CI.247.158; 10.CI.247.196;10.CI.247.223; 10.CI.247.240; 10.CI.247.244; 10.CI.247.243;10.CI.247.247; Prodrugs of 10.CO 10.CO.4.157; 10.CO.4.158; 10.CO.4.196;10.CO.4.223; 10.CO.4.240; 10.CO.4.244; 10.CO.4.243; 10.CO.4.247;10.CO.5.157; 10.CO.5.158; 10.CO.5.196; 10.CO.5.223; 10.CO.5.240;10.CO.5.244; 10.CO.5.243; 10.CO.5.247; 10.CO.7.157; 10.CO.7.158;10.CO.7.196; 10.CO.7.223; 10.CO.7.240; 10.CO.7.244; 10.CO.7.243;10.CO.7.247; 10.CO.15.157; 10.CO.15.158; 10.CO.15.196; 10.CO.15.223;10.CO.15.240; 10.CO.15.244; 10.CO.15.243; 10.CO.15.247; 10.CO.16.157;10.CO.16.158; 10.CO.16.196; 10.CO.16.223; 10.CO.16.240; 10.CO.16.244;10.CO.16.243; 10.CO.16.247; 10.CO.18.157; 10.CO.18.158; 10.CO.18.196;10.CO.18.223; 10.CO.18.240; 10.CO.18.244; 10.CO.18.243; 10.CO.18.247;10.CO.26.157; 10.CO.26.158; 10.CO.26.196; 10.CO.26.223; 10.CO.26.240;10.CO.26.244; 10.CO.26.243; 10.CO.26.247; 10.CO.27.157; 10.CO.27.158;10.CO.27.196; 10.CO.27.223; 10.CO.27.240; 10.CO.27.244; 10.CO.27.243;10.CO.27.247; 10.CO.29.157; 10.CO.29.158; 10.CO.29.196; 10.CO.29.223;10.CO.29.240; 10.CO.29.244; 10.CO.29.243; 10.CO.29.247; 10.CO.54.157;10.CO.54.158; 10.CO.54.196; 10.CO.54.223; 10.CO.54.240; 10.CO.54.244;10.CO.54.243; 10.CO.54.247; 10.CO.55.157; 10.CO.55.158; 10.CO.55.196;10.CO.55.223; 10.CO.55.240; 10.CO.55.244; 10.CO.55.243; 10.CO.55.247;10.CO.56.157; 10.CO.56.158; 10.CO.56.196; 10.CO.56.223; 10.CO.56.240;10.CO.56.244; 10.CO.56.243; 10.CO.56.247; 10.CO.157.157; 10.CO.157.158;10.CO.157.196; 10.CO.157.223; 10.CO.157.240; 10.CO.157.244;10.CO.157.243; 10.CO.157.247; 10.CO.196.157; 10.CO.196.158;10.CO.196.196; 10.CO.196.223; 10.CO.196.240; 10.CO.196.244;10.CO.196.243; 10.CO.196.247; 10.CO.223.157; 10.CO.223.158;10.CO.223.196; 10.CO.223.223; 10.CO.223.240; 10.CO.223.244;10.CO.223.243; 10.CO.223.247; 10.CO.240.157; 10.CO.240.158;10.CO.240.196; 10.CO.240.223; 10.CO.240.240; 10.CO.240.244;10.CO.240.243; 10.CO.240.247; 10.CO.244.157; 10.CO.244.158;10.CO.244.196; 10.CO.244.223; 10.CO.244.240; 10.CO.244.244;10.CO.244.243; 10.CO.244.247; 10.CO.247.157; 10.CO.247.158;10.CO.247.196; 10.CO.247.223; 10.CO.247.240; 10.CO.247.244;10.CO.247.243; 10.CO.247.247; Prodrugs of 11.AH 11.AH.4.157;11.AH.4.158; 11.AH.4.196; 11.AH.4.223; 11.AH.4.240; 11.AH.4.244;11.AH.4.243; 11.AH.4.247; 11.AH.5.157; 11.AH.5.158; 11.AH.5.196;11.AH.5.223; 11.AH.5.240; 11.AH.5.244; 11.AH.5.243; 11.AH.5.247;11.AH.7.157; 11.AH.7.158; 11.AH.7.196; 11.AH.7.223; 11.AH.7.240;11.AH.7.244; 11.AH.7.243; 11.AH.7.247; 11.AH.15.157; 11.AH.15.158;11.AH.15.196; 11.AH.15.223; 11.AH.15.240; 11.AH.15.244; 11.AH.15.243;11.AH.15.247; 11.AH.16.157; 11.AH.16.158; 11.AH.16.196; 11.AH.16.223;11.AH.16.240; 11.AH.16.244; 11.AH.16.243; 11.AH.16.247; 11.AH.18.157;11.AH.18.158; 11.AH.18.196; 11.AH.18.223; 11.AH.18.240; 11.AH.18.244;11.AH.18.243; 11.AH.18.247; 11.AH.26.157; 11.AH.26.158; 11.AH.26.196;11.AH.26.223; 11.AH.26.240; 11.AH.26.244; 11.AH.26.243; 11.AH.26.247;11.AH.27.157; 11.AH.27.158; 11.AH.27.196; 11.AH.27.223; 11.AH.27.240;11.AH.27.244; 11.AH.27.243; 11.AH.27.247; 11.AH.29.157; 11.AH.29.158;11.AH.29.196; 11.AH.29.223; 11.AH.29.240; 11.AH.29.244; 11.AH.29.243;11.AH.29.247; 11.AH.54.157; 11.AH.54.158; 11.AH.54.196; 11.AH.54.223;11.AH.54.240; 11.AH.54.244; 11.AH.54.243; 11.AH.54.247; 11.AH.55.157;11.AH.55.158; 11.AH.55.196; 11.AH.55.223; 11.AH.55.240; 11.AH.55.244;11.AH.55.243; 11.AH.55.247; 11.AH.56.157; 11.AH.56.158; 11.AH.56.196;11.AH.56.223; 11.AH.56.240; 11.AH.56.244; 11.AH.56.243; 11.AH.56.247;11.AH.157.157; 11.AH.157.158; 11.AH.157.196; 11.AH.157.223;11.AH.157.240; 11.AH.157.244; 11.AH.157.243; 11.AH.157.247;11.AH.196.157; 11.AH.196.158; 11.AH.196.196; 11.AH.196.223;11.AH.196.240; 11.AH.196.244; 11.AH.196.243; 11.AH.196.247;11.AH.223.157; 11.AH.223.158; 11.AH.223.196; 11.AH.223.223;11.AH.223.240; 11.AH.223.244; 11.AH.223.243; 11.AH.223.247;11.AH.240.157; 11.AH.240.158; 11.AH.240.196; 11.AH.240.223;11.AH.240.240; 11.AH.240.244; 11.AH.240.243; 11.AH.240.247;11.AH.244.157; 11.AH.244.158; 11.AH.244.196; 11.AH.244.223;11.AH.244.240; 11.AH.244.244; 11.AH.244.243; 11.AH.244.247;11.AH.247.157; 11.AH.247.158; 11.AH.247.196; 11.AH.247.223;11.AH.247.240; 11.AH.247.244; 11.AH.247.243; 11.AH.247.247; Prodrugs of11.AJ 11.AJ.4.157; 11.AJ.4.158; 11.AJ.4.196; 11.AJ.4.223; 11.AJ.4.240;11.AJ.4.244; 11.AJ.4.243; 11.AJ.4.247; 11.AJ.5.157; 11.AJ.5.158;11.AJ.5.196; 11.AJ.5.223; 11.AJ.5.240; 11.AJ.5.244; 11.AJ.5.243;11.AJ.5.247; 11.AJ.7.157; 11.AJ.7.158; 11.AJ.7.196; 11.AJ.7.223;11.AJ.7.240; 11.AJ.7.244; 11.AJ.7.243; 11.AJ.7.247; 11.AJ.15.157;11.AJ.15.158; 11.AJ.15.196; 11.AJ.15.223; 11.AJ.15.240; 11.AJ.15.244;11.AJ.15.243; 11.AJ.15.247; 11.AJ.16.157; 11.AJ.16.158; 11.AJ.16.196;11.AJ.16.223; 11.AJ.16.240; 11.AJ.16.244; 11.AJ.16.243; 11.AJ.16.247;11.AJ.18.157; 11.AJ.18.158; 11.AJ.18.196; 11.AJ.18.223; 11.AJ.18.240;11.AJ.18.244; 11.AJ.18.243; 11.AJ.18.247; 11.AJ.26.157; 11.AJ.26.158;11.AJ.26.196; 11.AJ.26.223; 11.AJ.26.240; 11.AJ.26.244; 11.AJ.26.243;11.AJ.26.247; 11.AJ.27.157; 11.AJ.27.158; 11.AJ.27.196; 11.AJ.27.223;11.AJ.27.240; 11.AJ.27.244; 11.AJ.27.243; 11.AJ.27.247; 11.AJ.29.157;11.AJ.29.158; 11.AJ.29.196; 11.AJ.29.223; 11.AJ.29.240; 11.AJ.29.244;11.AJ.29.243; 11.AJ.29.247; 11.AJ.54.157; 11.AJ.54.158; 11.AJ.54.196;11.AJ.54.223; 11.AJ.54.240; 11.AJ.54.244; 11.AJ.54.243; 11.AJ.54.247;11.AJ.55.157; 11.AJ.55.158; 11.AJ.55.196; 11.AJ.55.223; 11.AJ.55.240;11.AJ.55.244; 11.AJ.55.243; 11.AJ.55.247; 11.AJ.56.157; 11.AJ.56.158;11.AJ.56.196; 11.AJ.56.223; 11.AJ.56.240; 11.AJ.56.244; 11.AJ.56.243;11.AJ.56.247; 11.AJ.157.157; 11.AJ.157.158; 11.AJ.157.196;11.AJ.157.223; 11.AJ.157.240; 11.AJ.157.244; 11.AJ.157.243;11.AJ.157.247; 11.AJ.196.157; 11.AJ.196.158; 11.AJ.196.196;11.AJ.196.223; 11.AJ.196.240; 11.AJ.196.244; 11.AJ.196.243;11.AJ.196.247; 11.AJ.223.157; 11.AJ.223.158; 11.AJ.223.196;11.AJ.223.223; 11.AJ.223.240; 11.AJ.223.244; 11.AJ.223.243;11.AJ.223.247; 11.AJ.240.157; 11.AJ.240.158; 11.AJ.240.196;11.AJ.240.223; 11.AJ.240.240; 11.AJ.240.244; 11.AJ.240.243;11.AJ.240.247; 11.AJ.244.157; 11.AJ.244.158; 11.AJ.244.196;11.AJ.244.223; 11.AJ.244.240; 11.AJ.244.244; 11.AJ.244.243;11.AJ.244.247; 11.AJ.247.157; 11.AJ.247.158; 11.AJ.247.196;11.AJ.247.223; 11.AJ.247.240; 11.AJ.247.244; 11.AJ.247.243;11.AJ.247.247; Prodrugs of 11.AN 11.AN.4.157; 11.AN.4.158; 11.AN.4.196;11.AN.4.223; 11.AN.4.240; 11.AN.4.244; 11.AN.4.243; 11.AN.4.247;11.AN.5.157; 11.AN.5.158; 11.AN.5.196; 11.AN.5.223; 11.AN.5.240;11.AN.5.244; 11.AN.5.243; 11.AN.5.247; 11.AN.7.157; 11.AN.7.158;11.AN.7.196; 11.AN.7.223; 11.AN.7.240; 11.AN.7.244; 11.AN.7.243;11.AN.7.247; 11.AN.15.157; 11.AN.15.158; 11.AN.15.196; 11.AN.15.223;11.AN.15.240; 11.AN.15.244; 11.AN.15.243; 11.AN.15.247; 11.AN.16.157;11.AN.16.158; 11.AN.16.196; 11.AN.16.223; 11.AN.16.240; 11.AN.16.244;11.AN.16.243; 11.AN.16.247; 11.AN.18.157; 11.AN.18.158; 11.AN.18.196;11.AN.18.223; 11.AN.18.240; 11.AN.18.244; 11.AN.18.243; 11.AN.18.247;11.AN.26.157; 11.AN.26.158; 11.AN.26.196; 11.AN.26.223; 11.AN.26.240;11.AN.26.244; 11.AN.26.243; 11.AN.26.247; 11.AN.27.157; 11.AN.27.158;11.AN.27.196; 11.AN.27.223; 11.AN.27.240; 11.AN.27.244; 11.AN.27.243;11.AN.27.247; 11.AN.29.157; 11.AN.29.158; 11.AN.29.196; 11.AN.29.223;11.AN.29.240; 11.AN.29.244; 11.AN.29.243; 11.AN.29.247; 11.AN.54.157;11.AN.54.158; 11.AN.54.196; 11.AN.54.223; 11.AN.54.240; 11.AN.54.244;11.AN.54.243; 11.AN.54.247; 11.AN.55.157; 11.AN.55.158; 11.AN.55.196;11.AN.55.223; 11.AN.55.240; 11.AN.55.244; 11.AN.55.243; 11.AN.55.247;11.AN.56.157; 11.AN.56.158; 11.AN.56.196; 11.AN.56.223; 11.AN.56.240;11.AN.56.244; 11.AN.56.243; 11.AN.56.247; 11.AN.157.157; 11.AN.157.158;11.AN.157.196; 11.AN.157.223; 11.AN.157.240; 11.AN.157.244;11.AN.157.243; 11.AN.157.247; 11.AN.196.157; 11.AN.196.158;11.AN.196.196; 11.AN.196.223; 11.AN.196.240; 11.AN.196.244;11.AN.196.243; 11.AN.196.247; 11.AN.223.157; 11.AN.223.158;11.AN.223.196; 11.AN.223.223; 11.AN.223.240; 11.AN.223.244;11.AN.223.243; 11.AN.223.247; 11.AN.240.157; 11.AN.240.158;11.AN.240.196; 11.AN.240.223; 11.AN.240.240; 11.AN.240.244;11.AN.240.243; 11.AN.240.247; 11.AN.244.157; 11.AN.244.158;11.AN.244.196; 11.AN.244.223; 11.AN.244.240; 11.AN.244.244;11.AN.244.243; 11.AN.244.247; 11.AN.247.157; 11.AN.247.158;11.AN.247.196; 11.AN.247.223; 11.AN.247.240; 11.AN.247.244;11.AN.247.243; 11.AN.247.247; Prodrugs of 11.AP 11.AP.4.157;11.AP.4.158; 11.AP.4.196; 11.AP.4.223; 11.AP.4.240; 11.AP.4.244;11.AP.4.243; 11.AP.4.247; 11.AP.5.157; 11.AP.5.158; 11.AP.5.196;11.AP.5.223; 11.AP.5.240; 11.AP.5.244; 11.AP.5.243; 11.AP.5.247;11.AP.7.157; 11.AP.7.158; 11.AP.7.196; 11.AP.7.223; 11.AP.7.240;11.AP.7.244; 11.AP.7.243; 11.AP.7.247; 11.AP.15.157; 11.AP.15.158;11.AP.15.196; 11.AP.15.223; 11.AP.15.240; 11.AP.15.244; 11.AP.15.243;11.AP.15.247; 11.AP.16.157; 11.AP.16.158; 11.AP.16.196; 11.AP.16.223;11.AP.16.240; 11.AP.16.244; 11.AP.16.243; 11.AP.16.247; 11.AP.18.157;11.AP.18.158; 11.AP.18.196; 11.AP.18.223; 11.AP.18.240; 11.AP.18.244;11.AP.18.243; 11.AP.18.247; 11.AP.26.157; 11.AP.26.158; 11.AP.26.196;11.AP.26.223; 11.AP.26.240; 11.AP.26.244; 11.AP.26.243; 11.AP.26.247;11.AP.27.157; 11.AP.27.158; 11.AP.27.196; 11.AP.27.223; 11.AP.27.240;11.AP.27.244; 11.AP.27.243; 11.AP.27.247; 11.AP.29.157; 11.AP.29.158;11.AP.29.196; 11.AP.29.223; 11.AP.29.240; 11.AP.29.244; 11.AP.29.243;11.AP.29.247; 11.AP.54.157; 11.AP.54.158; 11.AP.54.196; 11.AP.54.223;11.AP.54.240; 11.AP.54.244; 11.AP.54.243; 11.AP.54.247; 11.AP.55.157;11.AP.55.158; 11.AP.55.196; 11.AP.55.223; 11.AP.55.240; 11.AP.55.244;11.AP.55.243; 11.AP.55.247; 11.AP.56.157; 11.AP.56.158; 11.AP.56.196;11.AP.56.223; 11.AP.56.240; 11.AP.56.244; 11.AP.56.243; 11.AP.56.247;11.AP.157.157; 11.AP.157.158; 11.AP.157.196; 11.AP.157.223;11.AP.157.240; 11.AP.157.244; 11.AP.157.243; 11.AP.157.247;11.AP.196.157; 11.AP.196.158; 11.AP.196.196; 11.AP.196.223;11.AP.196.240; 11.AP.196.244; 11.AP.196.243; 11.AP.196.247;11.AP.223.157; 11.AP.223.158; 11.AP.223.196; 11.AP.223.223;11.AP.223.240; 11.AP.223.244; 11.AP.223.243; 11.AP.223.247;11.AP.240.157; 11.AP.240.158; 11.AP.240.196; 11.AP.240.223;11.AP.240.240; 11.AP.240.244; 11.AP.240.243; 11.AP.240.247;11.AP.244.157; 11.AP.244.158; 11.AP.244.196; 11.AP.244.223;11.AP.244.240; 11.AP.244.244; 11.AP.244.243; 11.AP.244.247;11.AP.247.157; 11.AP.247.158; 11.AP.247.196; 11.AP.247.223;11.AP.247.240; 11.AP.247.244; 11.AP.247.243; 11.AP.247.247; Prodrugs of11.AZ 11.AZ.4.157; 11.AZ.4.158; 11.AZ.4.196; 11.AZ.4.223; 11.AZ.4.240;11.AZ.4.244; 11.AZ.4.243; 11.AZ.4.247; 11.AZ.5.157; 11.AZ.5.158;11.AZ.5.196; 11.AZ.5.223; 11.AZ.5.240; 11.AZ.5.244; 11.AZ.5.243;11.AZ.5.247; 11.AZ.7.157; 11.AZ.7.158; 11.AZ.7.196; 11.AZ.7.223;11.AZ.7.240; 11.AZ.7.244; 11.AZ.7.243; 11.AZ.7.247; 11.AZ.15.157;11.AZ.15.158; 11.AZ.15.196; 11.AZ.15.223; 11.AZ.15.240; 11.AZ.15.244;11.AZ.15.243; 11.AZ.15.247; 11.AZ.16.157; 11.AZ.16.158; 11.AZ.16.196;11.AZ.16.223; 11.AZ.16.240; 11.AZ.16.244; 11.AZ.16.243; 11.AZ.16.247;11.AZ.18.157; 11.AZ.18.158; 11.AZ.18.196; 11.AZ.18.223; 11.AZ.18.240;11.AZ.18.244; 11.AZ.18.243; 11.AZ.18.247; 11.AZ.26.157; 11.AZ.26.158;11.AZ.26.196; 11.AZ.26.223; 11.AZ.26.240; 11.AZ.26.244; 11.AZ.26.243;11.AZ.26.247; 11.AZ.27.157; 11.AZ.27.158; 11.AZ.27.196; 11.AZ.27.223;11.AZ.27.240; 11.AZ.27.244; 11.AZ.27.243; 11.AZ.27.247; 11.AZ.29.157;11.AZ.29.158; 11.AZ.29.196; 11.AZ.29.223; 11.AZ.29.240; 11.AZ.29.244;11.AZ.29.243; 11.AZ.29.247; 11.AZ.54.157; 11.AZ.54.158; 11.AZ.54.196;11.AZ.54.223; 11.AZ.54.240; 11.AZ.54.244; 11.AZ.54.243; 11.AZ.54.247;11.AZ.55.157; 11.AZ.55.158; 11.AZ.55.196; 11.AZ.55.223; 11.AZ.55.240;11.AZ.55.244; 11.AZ.55.243; 11.AZ.55.247; 11.AZ.56.157; 11.AZ.56.158;11.AZ.56.196; 11.AZ.56.223; 11.AZ.56.240; 11.AZ.56.244; 11.AZ.56.243;11.AZ.56.247; 11.AZ.157.157; 11.AZ.157.158; 11.AZ.157.196;11.AZ.157.223; 11.AZ.157.240; 11.AZ.157.244; 11.AZ.157.243;11.AZ.157.247; 11.AZ.196.157; 11.AZ.196.158; 11.AZ.196.196;11.AZ.196.223; 11.AZ.196.240; 11.AZ.196.244; 11.AZ.196.243;11.AZ.196.247; 11.AZ.223.157; 11.AZ.223.158; 11.AZ.223.196;11.AZ.223.223; 11.AZ.223.240; 11.AZ.223.244; 11.AZ.223.243;11.AZ.223.247; 11.AZ.240.157; 11.AZ.240.158; 11.AZ.240.196;11.AZ.240.223; 11.AZ.240.240; 11.AZ.240.244; 11.AZ.240.243;11.AZ.240.247; 11.AZ.244.157; 11.AZ.244.158; 11.AZ.244.196;11.AZ.244.223; 11.AZ.244.240; 11.AZ.244.244; 11.AZ.244.243;11.AZ.244.247; 11.AZ.247.157; 11.AZ.247.158; 11.AZ.247.196;11.AZ.247.223; 11.AZ.247.240; 11.AZ.247.244; 11.AZ.247.243;11.AZ.247.247; Prodrugs of 11.BF 11.BF.4.157; 11.BF.4.158; 11.BF.4.196;11.BF.4.223; 11.BF.4.240; 11.BF.4.244; 11.BF.4.243; 11.BF.4.247;11.BF.5.157; 11.BF.5.158; 11.BF.5.196; 11.BF.5.223; 11.BF.5.240;11.BF.5.244; 11.BF.5.243; 11.BF.5.247; 11.BF.7.157; 11.BF.7.158;11.BF.7.196; 11.BF.7.223; 11.BF.7.240; 11.BF.7.244; 11.BF.7.243;11.BF.7.247; 11.BF.15.157; 11.BF.15.158; 11.BF.15.196; 11.BF.15.223;11.BF.15.240; 11.BF.15.244; 11.BF.15.243; 11.BF.15.247; 11.BF.16.157;11.BF.16.158; 11.BF.16.196; 11.BF.16.223; 11.BF.16.240; 11.BF.16.244;11.BF.16.243; 11.BF.16.247; 11.BF.18.157; 11.BF.18.158; 11.BF.18.196;11.BF.18.223; 11.BF.18.240; 11.BF.18.244; 11.BF.18.243; 11.BF.18.247;11.BF.26.157; 11.BF.26.158; 11.BF.26.196; 11.BF.26.223; 11.BF.26.240;11.BF.26.244; 11.BF.26.243; 11.BF.26.247; 11.BF.27.157; 11.BF.27.158;11.BF.27.196; 11.BF.27.223; 11.BF.27.240; 11.BF.27.244; 11.BF.27.243;11.BF.27.247; 11.BF.29.157; 11.BF.29.158; 11.BF.29.196; 11.BF.29.223;11.BF.29.240; 11.BF.29.244; 11.BF.29.243; 11.BF.29.247; 11.BF.54.157;11.BF.54.158; 11.BF.54.196; 11.BF.54.223; 11.BF.54.240; 11.BF.54.244;11.BF.54.243; 11.BF.54.247; 11.BF.55.157; 11.BF.55.158; 11.BF.55.196;11.BF.55.223; 11.BF.55.240; 11.BF.55.244; 11.BF.55.243; 11.BF.55.247;11.BF.56.157; 11.BF.56.158; 11.BF.56.196; 11.BF.56.223; 11.BF.56.240;11.BF.56.244; 11.BF.56.243; 11.BF.56.247; 11.BF.157.157; 11.BF.157.158;11.BF.157.196; 11.BF.157.223; 11.BF.157.240; 11.BF.157.244;11.BF.157.243; 11.BF.157.247; 11.BF.196.157; 11.BF.196.158;11.BF.196.196; 11.BF.196.223; 11.BF.196.240; 11.BF.196.244;11.BF.196.243; 11.BF.196.247; 11.BF.223.157; 11.BF.223.158;11.BF.223.196; 11.BF.223.223; 11.BF.223.240; 11.BF.223.244;11.BF.223.243; 11.BF.223.247; 11.BF.240.157; 11.BF.240.158;11.BF.240.196; 11.BF.240.223; 11.BF.240.240; 11.BF.240.244;11.BF.240.243; 11.BF.240.247; 11.BF.244.157; 11.BF.244.158;11.BF.244.196; 11.BF.244.223; 11.BF.244.240; 11.BF.244.244;11.BF.244.243; 11.BF.244.247; 11.BF.247.157; 11.BF.247.158;11.BF.247.196; 11.BF.247.223; 11.BF.247.240; 11.BF.247.244;11.BF.247.243; 11.BF.247.247; Prodrugs of 11.CI 11.CI.4.157;11.CI.4.158; 11.CI.4.196; 11.CI.4.223; 11.CI.4.240; 11.CI.4.244;11.CI.4.243; 11.CI.4.247; 11.CI.5.157; 11.CI.5.158; 11.CI.5.196;11.CI.5.223; 11.CI.5.240; 11.CI.5.244; 11.CI.5.243; 11.CI.5.247;11.CI.7.157; 11.CI.7.158; 11.CI.7.196; 11.CI.7.223; 11.CI.7.240;11.CI.7.244; 11.CI.7.243; 11.CI.7.247; 11.CI.15.157; 11.CI.15.158;11.CI.15.196; 11.CI.15.223; 11.CI.15.240; 11.CI.15.244; 11.CI.15.243;11.CI.15.247; 11.CI.16.157; 11.CI.16.158; 11.CI.16.196; 11.CI.16.223;11.CI.16.240; 11.CI.16.244; 11.CI.16.243; 11.CI.16.247; 11.CI.18.157;11.CI.18.158; 11.CI.18.196; 11.CI.18.223; 11.CI.18.240; 11.CI.18.244;11.CI.18.243; 11.CI.18.247; 11.CI.26.157; 11.CI.26.158; 11.CI.26.196;11.CI.26.223; 11.CI.26.240; 11.CI.26.244; 11.CI.26.243; 11.CI.26.247;11.CI.27.157; 11.CI.27.158; 11.CI.27.196; 11.CI.27.223; 11.CI.27.240;11.CI.27.244; 11.CI.27.243; 11.CI.27.247; 11.CI.29.157; 11.CI.29.158;11.CI.29.196; 11.CI.29.223; 11.CI.29.240; 11.CI.29.244; 11.CI.29.243;11.CI.29.247; 11.CI.54.157; 11.CI.54.158; 11.CI.54.196; 11.CI.54.223;11.CI.54.240; 11.CI.54.244; 11.CI.54.243; 11.CI.54.247; 11.CI.55.157;11.CI.55.158; 11.CI.55.196; 11.CI.55.223; 11.CI.55.240; 11.CI.55.244;11.CI.55.243; 11.CI.55.247; 11.CI.56.157; 11.CI.56.158; 11.CI.56.196;11.CI.56.223; 11.CI.56.240; 11.CI.56.244; 11.CI.56.243; 11.CI.56.247;11.CI.157.157; 11.CI.157.158; 11.CI.157.196; 11.CI.157.223;11.CI.157.240; 11.CI.157.244; 11.CI.157.243; 11.CI.157.247;11.CI.196.157; 11.CI.196.158; 11.CI.196.196; 11.CI.196.223;11.CI.196.240; 11.CI.196.244; 11.CI.196.243; 11.CI.196.247;11.CI.223.157; 11.CI.223.158; 11.CI.223.196; 11.CI.223.223;11.CI.223.240; 11.CI.223.244; 11.CI.223.243; 11.CI.223.247;11.CI.240.157; 11.CI.240.158; 11.CI.240.196; 11.CI.240.223;11.CI.240.240; 11.CI.240.244; 11.CI.240.243; 11.CI.240.247;11.CI.244.157; 11.CI.244.158; 11.CI.244.196; 11.CI.244.223;11.CI.244.240; 11.CI.244.244; 11.CI.244.243; 11.CI.244.247;11.CI.247.157; 11.CI.247.158; 11.CI.247.196; 11.CI.247.223;11.CI.247.240; 11.CI.247.244; 11.CI.247.243; 11.CI.247.247; Prodrugs of11.CO 11.CO.4.157; 11.CO.4.158; 11.CO.4.196; 11.CO.4.223; 11.CO.4.240;11.CO.4.244; 11.CO.4.243; 11.CO.4.247; 11.CO.5.157; 11.CO.5.158;11.CO.5.196; 11.CO.5.223; 11.CO.5.240; 11.CO.5.244; 11.CO.5.243;11.CO.5.247; 11.CO.7.157; 11.CO.7.158; 11.CO.7.196; 11.CO.7.223;11.CO.7.240; 11.CO.7.244; 11.CO.7.243; 11.CO.7.247; 11.CO.15.157;11.CO.15.158; 11.CO.15.196; 11.CO.15.223; 11.CO.15.240; 11.CO.15.244;11.CO.15.243; 11.CO.15.247; 11.CO.16.157; 11.CO.16.158; 11.CO.16.196;11.CO.16.223; 11.CO.16.240; 11.CO.16.244; 11.CO.16.243; 11.CO.16.247;11.CO.18.157; 11.CO.18.158; 11.CO.18.196; 11.CO.18.223; 11.CO.18.240;11.CO.18.244; 11.CO.18.243; 11.CO.18.247; 11.CO.26.157; 11.CO.26.158;11.CO.26.196; 11.CO.26.223; 11.CO.26.240; 11.CO.26.244; 11.CO.26.243;11.CO.26.247; 11.CO.27.157; 11.CO.27.158; 11.CO.27.196; 11.CO.27.223;11.CO.27.240; 11.CO.27.244; 11.CO.27.243; 11.CO.27.247; 11.CO.29.157;11.CO.29.158; 11.CO.29.196; 11.CO.29.223; 11.CO.29.240; 11.CO.29.244;11.CO.29.243; 11.CO.29.247; 11.CO.54.157; 11.CO.54.158; 11.CO.54.196;11.CO.54.223; 11.CO.54.240; 11.CO.54.244; 11.CO.54.243; 11.CO.54.247;11.CO.55.157; 11.CO.55.158; 11.CO.55.196; 11.CO.55.223; 11.CO.55.240;11.CO.55.244; 11.CO.55.243; 11.CO.55.247; 11.CO.56.157; 11.CO.56.158;11.CO.56.196; 11.CO.56.223; 11.CO.56.240; 11.CO.56.244; 11.CO.56.243;11.CO.56.247; 11.CO.157.157; 11.CO.157.158; 11.CO.157.196;11.CO.157.223; 11.CO.157.240; 11.CO.157.244; 11.CO.157.243;11.CO.157.247; 11.CO.196.157; 11.CO.196.158; 11.CO.196.196;11.CO.196.223; 11.CO.196.240; 11.CO.196.244; 11.CO.196.243;11.CO.196.247; 11.CO.223.157; 11.CO.223.158; 11.CO.223.196;11.CO.223.223; 11.CO.223.240; 11.CO.223.244; 11.CO.223.243;11.CO.223.247; 11.CO.240.157; 11.CO.240.158; 11.CO.240.196;11.CO.240.223; 11.CO.240.240; 11.CO.240.244; 11.CO.240.243;11.CO.240.247; 11.CO.244.157; 11.CO.244.158; 11.CO.244.196;11.CO.244.223; 11.CO.244.240; 11.CO.244.244; 11.CO.244.243;11.CO.244.247; 11.CO.247.157; 11.CO.247.158; 11.CO.247.196;11.CO.247.223; 11.CO.247.240; 11.CO.247.244; 11.CO.247.243;11.CO.247.247; Prodrugs of 12.AH 12.AH.4.157; 12.AH.4.158; 12.AH.4.196;12.AH.4.223; 12.AH.4.240; 12.AH.4.244; 12.AH.4.243; 12.AH.4.247;12.AH.5.157; 12.AH.5.158; 12.AH.5.196; 12.AH.5.223; 12.AH.5.240;12.AH.5.244; 12.AH.5.243; 12.AH.5.247; 12.AH.7.157; 12.AH.7.158;12.AH.7.196; 12.AH.7.223; 12.AH.7.240; 12.AH.7.244; 12.AH.7.243;12.AH.7.247; 12.AH.15.157; 12.AH.15.158; 12.AH.15.196; 12.AH.15.223;12.AH.15.240; 12.AH.15.244; 12.AH.15.243; 12.AH.15.247; 12.AH.16.157;12.AH.16.158; 12.AH.16.196; 12.AH.16.223; 12.AH.16.240; 12.AH.16.244;12.AH.16.243; 12.AH.16.247; 12.AH.18.157; 12.AH.18.158; 12.AH.18.196;12.AH.18.223; 12.AH.18.240; 12.AH.18.244; 12.AH.18.243; 12.AH.18.247;12.AH.26.157; 12.AH.26.158; 12.AH.26.196; 12.AH.26.223; 12.AH.26.240;12.AH.26.244; 12.AH.26.243; 12.AH.26.247; 12.AH.27.157; 12.AH.27.158;12.AH.27.196; 12.AH.27.223; 12.AH.27.240; 12.AH.27.244; 12.AH.27.243;12.AH.27.247; 12.AH.29.157; 12.AH.29.158; 12.AH.29.196; 12.AH.29.223;12.AH.29.240; 12.AH.29.244; 12.AH.29.243; 12.AH.29.247; 12.AH.54.157;12.AH.54.158; 12.AH.54.196; 12.AH.54.223; 12.AH.54.240; 12.AH.54.244;12.AH.54.243; 12.AH.54.247; 12.AH.55.157; 12.AH.55.158; 12.AH.55.196;12.AH.55.223; 12.AH.55.240; 12.AH.55.244; 12.AH.55.243; 12.AH.55.247;12.AH.56.157; 12.AH.56.158; 12.AH.56.196; 12.AH.56.223; 12.AH.56.240;12.AH.56.244; 12.AH.56.243; 12.AH.56.247; 12.AH.157.157; 12.AH.157.158;12.AH.157.196; 12.AH.157.223; 12.AH.157.240; 12.AH.157.244;12.AH.157.243; 12.AH.157.247; 12.AH.196.157; 12.AH.196.158;12.AH.196.196; 12.AH.196.223; 12.AH.196.240; 12.AH.196.244;12.AH.196.243; 12.AH.196.247; 12.AH.223.157; 12.AH.223.158;12.AH.223.196; 12.AH.223.223; 12.AH.223.240; 12.AH.223.244;12.AH.223.243; 12.AH.223.247; 12.AH.240.157; 12.AH.240.158;12.AH.240.196; 12.AH.240.223; 12.AH.240.240; 12.AH.240.244;12.AH.240.243; 12.AH.240.247; 12.AH.244.157; 12.AH.244.158;12.AH.244.196; 12.AH.244.223; 12.AH.244.240; 12.AH.244.244;12.AH.244.243; 12.AH.244.247; 12.AH.247.157; 12.AH.247.158;12.AH.247.196; 12.AH.247.223; 12.AH.247.240; 12.AH.247.244;12.AH.247.243; 12.AH.247.247; Prodrugs of 12.AJ 12.AJ.4.157;12.AJ.4.158; 12.AJ.4.196; 12.AJ.4.223; 12.AJ.4.240; 12.AJ.4.244;12.AJ.4.243; 12.AJ.4.247; 12.AJ.5.157; 12.AJ.5.158; 12.AJ.5.196;12.AJ.5.223; 12.AJ.5.240; 12.AJ.5.244; 12.AJ.5.243; 12.AJ.5.247;12.AJ.7.157; 12.AJ.7.158; 12.AJ.7.196; 12.AJ.7.223; 12.AJ.7.240;12.AJ.7.244; 12.AJ.7.243; 12.AJ.7.247; 12.AJ.15.157; 12.AJ.15.158;12.AJ.15.196; 12.AJ.15.223; 12.AJ.15.240; 12.AJ.15.244; 12.AJ.15.243;12.AJ.15.247; 12.AJ.16.157; 12.AJ.16.158; 12.AJ.16.196; 12.AJ.16.223;12.AJ.16.240; 12.AJ.16.244; 12.AJ.16.243; 12.AJ.16.247; 12.AJ.18.157;12.AJ.18.158; 12.AJ.18.196; 12.AJ.18.223; 12.AJ.18.240; 12.AJ.18.244;12.AJ.18.243; 12.AJ.18.247; 12.AJ.26.157; 12.AJ.26.158; 12.AJ.26.196;12.AJ.26.223; 12.AJ.26.240; 12.AJ.26.244; 12.AJ.26.243; 12.AJ.26.247;12.AJ.27.157; 12.AJ.27.158; 12.AJ.27.196; 12.AJ.27.223; 12.AJ.27.240;12.AJ.27.244; 12.AJ.27.243; 12.AJ.27.247; 12.AJ.29.157; 12.AJ.29.158;12.AJ.29.196; 12.AJ.29.223; 12.AJ.29.240; 12.AJ.29.244; 12.AJ.29.243;12.AJ.29.247; 12.AJ.54.157; 12.AJ.54.158; 12.AJ.54.196; 12.AJ.54.223;12.AJ.54.240; 12.AJ.54.244; 12.AJ.54.243; 12.AJ.54.247; 12.AJ.55.157;12.AJ.55.158; 12.AJ.55.196; 12.AJ.55.223; 12.AJ.55.240; 12.AJ.55.244;12.AJ.55.243; 12.AJ.55.247; 12.AJ.56.157; 12.AJ.56.158; 12.AJ.56.196;12.AJ.56.223; 12.AJ.56.240; 12.AJ.56.244; 12.AJ.56.243; 12.AJ.56.247;12.AJ.157.157; 12.AJ.157.158; 12.AJ.157.196; 12.AJ.157.223;12.AJ.157.240; 12.AJ.157.244; 12.AJ.157.243; 12.AJ.157.247;12.AJ.196.157; 12.AJ.196.158; 12.AJ.196.196; 12.AJ.196.223;12.AJ.196.240; 12.AJ.196.244; 12.AJ.196.243; 12.AJ.196.247;12.AJ.223.157; 12.AJ.223.158; 12.AJ.223.196; 12.AJ.223.223;12.AJ.223.240; 12.AJ.223.244; 12.AJ.223.243; 12.AJ.223.247;12.AJ.240.157; 12.AJ.240.158; 12.AJ.240.196; 12.AJ.240.223;12.AJ.240.240; 12.AJ.240.244; 12.AJ.240.243; 12.AJ.240.247;12.AJ.244.157; 12.AJ.244.158; 12.AJ.244.196; 12.AJ.244.223;12.AJ.244.240; 12.AJ.244.244; 12.AJ.244.243; 12.AJ.244.247;12.AJ.247.157; 12.AJ.247.158; 12.AJ.247.196; 12.AJ.247.223;12.AJ.247.240; 12.AJ.247.244; 12.AJ.247.243; 12.AJ.247.247; Prodrugs of12.AN 12.AN.4.157; 12.AN.4.158; 12.AN.4.196; 12.AN.4.223; 12.AN.4.240;12.AN.4.244; 12.AN.4.243; 12.AN.4.247; 12.AN.5.157; 12.AN.5.158;12.AN.5.196; 12.AN.5.223; 12.AN.5.240; 12.AN.5.244; 12.AN.5.243;12.AN.5.247; 12.AN.7.157; 12.AN.7.158; 12.AN.7.196; 12.AN.7.223;12.AN.7.240; 12.AN.7.244; 12.AN.7.243; 12.AN.7.247; 12.AN.15.157;12.AN.15.158; 12.AN.15.196; 12.AN.15.223; 12.AN.15.240; 12.AN.15.244;12.AN.15.243; 12.AN.15.247; 12.AN.16.157; 12.AN.16.158; 12.AN.16.196;12.AN.16.223; 12.AN.16.240; 12.AN.16.244; 12.AN.16.243; 12.AN.16.247;12.AN.18.157; 12.AN.18.158; 12.AN.18.196; 12.AN.18.223; 12.AN.18.240;12.AN.18.244; 12.AN.18.243; 12.AN.18.247; 12.AN.26.157; 12.AN.26.158;12.AN.26.196; 12.AN.26.223; 12.AN.26.240; 12.AN.26.244; 12.AN.26.243;12.AN.26.247; 12.AN.27.157; 12.AN.27.158; 12.AN.27.196; 12.AN.27.223;12.AN.27.240; 12.AN.27.244; 12.AN.27.243; 12.AN.27.247; 12.AN.29.157;12.AN.29.158; 12.AN.29.196; 12.AN.29.223; 12.AN.29.240; 12.AN.29.244;12.AN.29.243; 12.AN.29.247; 12.AN.54.157; 12.AN.54.158; 12.AN.54.196;12.AN.54.223; 12.AN.54.240; 12.AN.54.244; 12.AN.54.243; 12.AN.54.247;12.AN.55.157; 12.AN.55.158; 12.AN.55.196; 12.AN.55.223; 12.AN.55.240;12.AN.55.244; 12.AN.55.243; 12.AN.55.247; 12.AN.56.157; 12.AN.56.158;12.AN.56.196; 12.AN.56.223; 12.AN.56.240; 12.AN.56.244; 12.AN.56.243;12.AN.56.247; 12.AN.157.157; 12.AN.157.158; 12.AN.157.196;12.AN.157.223; 12.AN.157.240; 12.AN.157.244; 12.AN.157.243;12.AN.157.247; 12.AN.196.157; 12.AN.196.158; 12.AN.196.196;12.AN.196.223; 12.AN.196.240; 12.AN.196.244; 12.AN.196.243;12.AN.196.247; 12.AN.223.157; 12.AN.223.158; 12.AN.223.196;12.AN.223.223; 12.AN.223.240; 12.AN.223.244; 12.AN.223.243;12.AN.223.247; 12.AN.240.157; 12.AN.240.158; 12.AN.240.196;12.AN.240.223; 12.AN.240.240; 12.AN.240.244; 12.AN.240.243;12.AN.240.247; 12.AN.244.157; 12.AN.244.158; 12.AN.244.196;12.AN.244.223; 12.AN.244.240; 12.AN.244.244; 12.AN.244.243;12.AN.244.247; 12.AN.247.157; 12.AN.247.158; 12.AN.247.196;12.AN.247.223; 12.AN.247.240; 12.AN.247.244; 12.AN.247.243;12.AN.247.247; Prodrugs of 12.AP 12.AP.4.157; 12.AP.4.158; 12.AP.4.196;12.AP.4.223; 12.AP.4.240; 12.AP.4.244; 12.AP.4.243; 12.AP.4.247;12.AP.5.157; 12.AP.5.158; 12.AP.5.196; 12.AP.5.223; 12.AP.5.240;12.AP.5.244; 12.AP.5.243; 12.AP.5.247; 12.AP.7.157; 12.AP.7.158;12.AP.7.196; 12.AP.7.223; 12.AP.7.240; 12.AP.7.244; 12.AP.7.243;12.AP.7.247; 12.AP.15.157; 12.AP.15.158; 12.AP.15.196; 12.AP.15.223;12.AP.15.240; 12.AP.15.244; 12.AP.15.243; 12.AP.15.247; 12.AP.16.157;12.AP.16.158; 12.AP.16.196; 12.AP.16.223; 12.AP.16.240; 12.AP.16.244;12.AP.16.243; 12.AP.16.247; 12.AP.18.157; 12.AP.18.158; 12.AP.18.196;12.AP.18.223; 12.AP.18.240; 12.AP.18.244; 12.AP.18.243; 12.AP.18.247;12.AP.26.157; 12.AP.26.158; 12.AP.26.196; 12.AP.26.223; 12.AP.26.240;12.AP.26.244; 12.AP.26.243; 12.AP.26.247; 12.AP.27.157; 12.AP.27.158;12.AP.27.196; 12.AP.27.223; 12.AP.27.240; 12.AP.27.244; 12.AP.27.243;12.AP.27.247; 12.AP.29.157; 12.AP.29.158; 12.AP.29.196; 12.AP.29.223;12.AP.29.240; 12.AP.29.244; 12.AP.29.243; 12.AP.29.247; 12.AP.54.157;12.AP.54.158; 12.AP.54.196; 12.AP.54.223; 12.AP.54.240; 12.AP.54.244;12.AP.54.243; 12.AP.54.247; 12.AP.55.157; 12.AP.55.158; 12.AP.55.196;12.AP.55.223; 12.AP.55.240; 12.AP.55.244; 12.AP.55.243; 12.AP.55.247;12.AP.56.157; 12.AP.56.158; 12.AP.56.196; 12.AP.56.223; 12.AP.56.240;12.AP.56.244; 12.AP.56.243; 12.AP.56.247; 12.AP.157.157; 12.AP.157.158;12.AP.157.196; 12.AP.157.223; 12.AP.157.240; 12.AP.157.244;12.AP.157.243; 12.AP.157.247; 12.AP.196.157; 12.AP.196.158;12.AP.196.196; 12.AP.196.223; 12.AP.196.240; 12.AP.196.244;12.AP.196.243; 12.AP.196.247; 12.AP.223.157; 12.AP.223.158;12.AP.223.196; 12.AP.223.223; 12.AP.223.240; 12.AP.223.244;12.AP.223.243; 12.AP.223.247; 12.AP.240.157; 12.AP.240.158;12.AP.240.196; 12.AP.240.223; 12.AP.240.240; 12.AP.240.244;12.AP.240.243; 12.AP.240.247; 12.AP.244.157; 12.AP.244.158;12.AP.244.196; 12.AP.244.223; 12.AP.244.240; 12.AP.244.244;12.AP.244.243; 12.AP.244.247; 12.AP.247.157; 12.AP.247.158;12.AP.247.196; 12.AP.247.223; 12.AP.247.240; 12.AP.247.244;12.AP.247.243; 12.AP.247.247; Prodrugs of 12.AZ 12.AZ.4.157;12.AZ.4.158; 12.AZ.4.196; 12.AZ.4.223; 12.AZ.4.240; 12.AZ.4.244;12.AZ.4.243; 12.AZ.4.247; 12.AZ.5.157; 12.AZ.5.158; 12.AZ.5.196;12.AZ.5.223; 12.AZ.5.240; 12.AZ.5.244; 12.AZ.5.243; 12.AZ.5.247;12.AZ.7.157; 12.AZ.7.158; 12.AZ.7.196; 12.AZ.7.223; 12.AZ.7.240;12.AZ.7.244; 12.AZ.7.243; 12.AZ.7.247; 12.AZ.15.157; 12.AZ.15.158;12.AZ.15.196; 12.AZ.15.223; 12.AZ.15.240; 12.AZ.15.244; 12.AZ.15.243;12.AZ.15.247; 12.AZ.16.157; 12.AZ.16.158; 12.AZ.16.196; 12.AZ.16.223;12.AZ.16.240; 12.AZ.16.244; 12.AZ.16.243; 12.AZ.16.247; 12.AZ.18.157;12.AZ.18.158; 12.AZ.18.196; 12.AZ.18.223; 12.AZ.18.240; 12.AZ.18.244;12.AZ.18.243; 12.AZ.18.247; 12.AZ.26.157; 12.AZ.26.158; 12.AZ.26.196;12.AZ.26.223; 12.AZ.26.240; 12.AZ.26.244; 12.AZ.26.243; 12.AZ.26.247;12.AZ.27.157; 12.AZ.27.158; 12.AZ.27.196; 12.AZ.27.223; 12.AZ.27.240;12.AZ.27.244; 12.AZ.27.243; 12.AZ.27.247; 12.AZ.29.157; 12.AZ.29.158;12.AZ.29.196; 12.AZ.29.223; 12.AZ.29.240; 12.AZ.29.244; 12.AZ.29.243;12.AZ.29.247; 12.AZ.54.157; 12.AZ.54.158; 12.AZ.54.196; 12.AZ.54.223;12.AZ.54.240; 12.AZ.54.244; 12.AZ.54.243; 12.AZ.54.247; 12.AZ.55.157;12.AZ.55.158; 12.AZ.55.196; 12.AZ.55.223; 12.AZ.55.240; 12.AZ.55.244;12.AZ.55.243; 12.AZ.55.247; 12.AZ.56.157; 12.AZ.56.158; 12.AZ.56.196;12.AZ.56.223; 12.AZ.56.240; 12.AZ.56.244; 12.AZ.56.243; 12.AZ.56.247;12.AZ.157.157; 12.AZ.157.158; 12.AZ.157.196; 12.AZ.157.223;12.AZ.157.240; 12.AZ.157.244; 12.AZ.157.243; 12.AZ.157.247;12.AZ.196.157; 12.AZ.196.158; 12.AZ.196.196; 12.AZ.196.223;12.AZ.196.240; 12.AZ.196.244; 12.AZ.196.243; 12.AZ.196.247;12.AZ.223.157; 12.AZ.223.158; 12.AZ.223.196; 12.AZ.223.223;12.AZ.223.240; 12.AZ.223.244; 12.AZ.223.243; 12.AZ.223.247;12.AZ.240.157; 12.AZ.240.158; 12.AZ.240.196; 12.AZ.240.223;12.AZ.240.240; 12.AZ.240.244; 12.AZ.240.243; 12.AZ.240.247;12.AZ.244.157; 12.AZ.244.158; 12.AZ.244.196; 12.AZ.244.223;12.AZ.244.240; 12.AZ.244.244; 12.AZ.244.243; 12.AZ.244.247;12.AZ.247.157; 12.AZ.247.158; 12.AZ.247.196; 12.AZ.247.223;12.AZ.247.240; 12.AZ.247.244; 12.AZ.247.243; 12.AZ.247.247; Prodrugs of12.BF 12.BF.4.157; 12.BF.4.158; 12.BF.4.196; 12.BF.4.223; 12.BF.4.240;12.BF.4.244; 12.BF.4.243; 12.BF.4.247; 12.BF.5.157; 12.BF.5.158;12.BF.5.196; 12.BF.5.223; 12.BF.5.240; 12.BF.5.244; 12.BF.5.243;12.BF.5.247; 12.BF.7.157; 12.BF.7.158; 12.BF.7.196; 12.BF.7.223;12.BF.7.240; 12.BF.7.244; 12.BF.7.243; 12.BF.7.247; 12.BF.15.157;12.BF.15.158; 12.BF.15.196; 12.BF.15.223; 12.BF.15.240; 12.BF.15.244;12.BF.15.243; 12.BF.15.247; 12.BF.16.157; 12.BF.16.158; 12.BF.16.196;12.BF.16.223; 12.BF.16.240; 12.BF.16.244; 12.BF.16.243; 12.BF.16.247;12.BF.18.157; 12.BF.18.158; 12.BF.18.196; 12.BF.18.223; 12.BF.18.240;12.BF.18.244; 12.BF.18.243; 12.BF.18.247; 12.BF.26.157; 12.BF.26.158;12.BF.26.196; 12.BF.26.223; 12.BF.26.240; 12.BF.26.244; 12.BF.26.243;12.BF.26.247; 12.BF.27.157; 12.BF.27.158; 12.BF.27.196; 12.BF.27.223;12.BF.27.240; 12.BF.27.244; 12.BF.27.243; 12.BF.27.247; 12.BF.29.157;12.BF.29.158; 12.BF.29.196; 12.BF.29.223; 12.BF.29.240; 12.BF.29.244;12.BF.29.243; 12.BF.29.247; 12.BF.54.157; 12.BF.54.158; 12.BF.54.196;12.BF.54.223; 12.BF.54.240; 12.BF.54.244; 12.BF.54.243; 12.BF.54.247;12.BF.55.157; 12.BF.55.158; 12.BF.55.196; 12.BF.55.223; 12.BF.55.240;12.BF.55.244; 12.BF.55.243; 12.BF.55.247; 12.BF.56.157; 12.BF.56.158;12.BF.56.196; 12.BF.56.223; 12.BF.56.240; 12.BF.56.244; 12.BF.56.243;12.BF.56.247; 12.BF.157.157; 12.BF.157.158; 12.BF.157.196;12.BF.157.223; 12.BF.157.240; 12.BF.157.244; 12.BF.157.243;12.BF.157.247; 12.BF.196.157; 12.BF.196.158; 12.BF.196.196;12.BF.196.223; 12.BF.196.240; 12.BF.196.244; 12.BF.196.243;12.BF.196.247; 12.BF.223.157; 12.BF.223.158; 12.BF.223.196;12.BF.223.223; 12.BF.223.240; 12.BF.223.244; 12.BF.223.243;12.BF.223.247; 12.BF.240.157; 12.BF.240.158; 12.BF.240.196;12.BF.240.223; 12.BF.240.240; 12.BF.240.244; 12.BF.240.243;12.BF.240.247; 12.BF.244.157; 12.BF.244.158; 12.BF.244.196;12.BF.244.223; 12.BF.244.240; 12.BF.244.244; 12.BF.244.243;12.BF.244.247; 12.BF.247.157; 12.BF.247.158; 12.BF.247.196;12.BF.247.223; 12.BF.247.240; 12.BF.247.244; 12.BF.247.243;12.BF.247.247; Prodrugs of 12.CI 12.CI.4.157; 12.CI.4.158; 12.CI.4.196;12.CI.4.223; 12.CI.4.240; 12.CI.4.244; 12.CI.4.243; 12.CI.4.247;12.CI.5.157; 12.CI.5.158; 12.CI.5.196; 12.CI.5.223; 12.CI.5.240;12.CI.5.244; 12.CI.5.243; 12.CI.5.247; 12.CI.7.157; 12.CI.7.158;12.CI.7.196; 12.CI.7.223; 12.CI.7.240; 12.CI.7.244; 12.CI.7.243;12.CI.7.247; 12.CI.15.157; 12.CI.15.158; 12.CI.15.196; 12.CI.15.223;12.CI.15.240; 12.CI.15.244; 12.CI.15.243; 12.CI.15.247; 12.CI.16.157;12.CI.16.158; 12.CI.16.196; 12.CI.16.223; 12.CI.16.240; 12.CI.16.244;12.CI.16.243; 12.CI.16.247; 12.CI.18.157; 12.CI.18.158; 12.CI.18.196;12.CI.18.223; 12.CI.18.240; 12.CI.18.244; 12.CI.18.243; 12.CI.18.247;12.CI.26.157; 12.CI.26.158; 12.CI.26.196; 12.CI.26.223; 12.CI.26.240;12.CI.26.244; 12.CI.26.243; 12.CI.26.247; 12.CI.27.157; 12.CI.27.158;12.CI.27.196; 12.CI.27.223; 12.CI.27.240; 12.CI.27.244; 12.CI.27.243;12.CI.27.247; 12.CI.29.157; 12.CI.29.158; 12.CI.29.196; 12.CI.29.223;12.CI.29.240; 12.CI.29.244; 12.CI.29.243; 12.CI.29.247; 12.CI.54.157;12.CI.54.158; 12.CI.54.196; 12.CI.54.223; 12.CI.54.240; 12.CI.54.244;12.CI.54.243; 12.CI.54.247; 12.CI.55.157; 12.CI.55.158; 12.CI.55.196;12.CI.55.223; 12.CI.55.240; 12.CI.55.244; 12.CI.55.243; 12.CI.55.247;12.CI.56.157; 12.CI.56.158; 12.CI.56.196; 12.CI.56.223; 12.CI.56.240;12.CI.56.244; 12.CI.56.243; 12.CI.56.247; 12.CI.157.157; 12.CI.157.158;12.CI.157.196; 12.CI.157.223; 12.CI.157.240; 12.CI.157.244;12.CI.157.243; 12.CI.157.247; 12.CI.196.157; 12.CI.196.158;12.CI.196.196; 12.CI.196.223; 12.CI.196.240; 12.CI.196.244;12.CI.196.243; 12.CI.196.247; 12.CI.223.157; 12.CI.223.158;12.CI.223.196; 12.CI.223.223; 12.CI.223.240; 12.CI.223.244;12.CI.223.243; 12.CI.223.247; 12.CI.240.157; 12.CI.240.158;12.CI.240.196; 12.CI.240.223; 12.CI.240.240; 12.CI.240.244;12.CI.240.243; 12.CI.240.247; 12.CI.244.157; 12.CI.244.158;12.CI.244.196; 12.CI.244.223; 12.CI.244.240; 12.CI.244.244;12.CI.244.243; 12.CI.244.247; 12.CI.247.157; 12.CI.247.158;12.CI.247.196; 12.CI.247.223; 12.CI.247.240; 12.CI.247.244;12.CI.247.243; 12.CI.247.247; Prodrugs of 12.CO 12.CO.4.157;12.CO.4.158; 12.CO.4.196; 12.CO.4.223; 12.CO.4.240; 12.CO.4.244;12.CO.4.243; 12.CO.4.247; 12.CO.5.157; 12.CO.5.158; 12.CO.5.196;12.CO.5.223; 12.CO.5.240; 12.CO.5.244; 12.CO.5.243; 12.CO.5.247;12.CO.7.157; 12.CO.7.158; 12.CO.7.196; 12.CO.7.223; 12.CO.7.240;12.CO.7.244; 12.CO.7.243; 12.CO.7.247; 12.CO.15.157; 12.CO.15.158;12.CO.15.196; 12.CO.15.223; 12.CO.15.240; 12.CO.15.244; 12.CO.15.243;12.CO.15.247; 12.CO.16.157; 12.CO.16.158; 12.CO.16.196; 12.CO.16.223;12.CO.16.240; 12.CO.16.244; 12.CO.16.243; 12.CO.16.247; 12.CO.18.157;12.CO.18.158; 12.CO.18.196; 12.CO.18.223; 12.CO.18.240; 12.CO.18.244;12.CO.18.243; 12.CO.18.247; 12.CO.26.157; 12.CO.26.158; 12.CO.26.196;12.CO.26.223; 12.CO.26.240; 12.CO.26.244; 12.CO.26.243; 12.CO.26.247;12.CO.27.157; 12.CO.27.158; 12.CO.27.196; 12.CO.27.223; 12.CO.27.240;12.CO.27.244; 12.CO.27.243; 12.CO.27.247; 12.CO.29.157; 12.CO.29.158;12.CO.29.196; 12.CO.29.223; 12.CO.29.240; 12.CO.29.244; 12.CO.29.243;12.CO.29.247; 12.CO.54.157; 12.CO.54.158; 12.CO.54.196; 12.CO.54.223;12.CO.54.240; 12.CO.54.244; 12.CO.54.243; 12.CO.54.247; 12.CO.55.157;12.CO.55.158; 12.CO.55.196; 12.CO.55.223; 12.CO.55.240; 12.CO.55.244;12.CO.55.243; 12.CO.55.247; 12.CO.56.157; 12.CO.56.158; 12.CO.56.196;12.CO.56.223; 12.CO.56.240; 12.CO.56.244; 12.CO.56.243; 12.CO.56.247;12.CO.157.157; 12.CO.157.158; 12.CO.157.196; 12.CO.157.223;12.CO.157.240; 12.CO.157.244; 12.CO.157.243; 12.CO.157.247;12.CO.196.157; 12.CO.196.158; 12.CO.196.196; 12.CO.196.223;12.CO.196.240; 12.CO.196.244; 12.CO.196.243; 12.CO.196.247;12.CO.223.157; 12.CO.223.158; 12.CO.223.196; 12.CO.223.223;12.CO.223.240; 12.CO.223.244; 12.CO.223.243; 12.CO.223.247;12.CO.240.157; 12.CO.240.158; 12.CO.240.196; 12.CO.240.223;12.CO.240.240; 12.CO.240.244; 12.CO.240.243; 12.CO.240.247;12.CO.244.157; 12.CO.244.158; 12.CO.244.196; 12.CO.244.223;12.CO.244.240; 12.CO.244.244; 12.CO.244.243; 12.CO.244.247;12.CO.247.157; 12.CO.247.158; 12.CO.247.196; 12.CO.247.223;12.CO.247.240; 12.CO.247.244; 12.CO.247.243; 12.CO.247.247. Prodrugs of13.B 13.B.228.228; 13.B.228.229; 13.B.228.230; 13.B.228.231;13.B.228.236; 13.B.228.237; 13.B.228.238; 13.B.228.239; 13.B.228.154;13.B.228.157; 13.B.228.166; 13.B.228.169; 13.B.228.172; 13.B.228.175;13.B.228.240; 13.B.228.244; 13.B.229.228; 13.B.229.229; 13.B.229.230;13.B.229.231; 13.B.229.236; 13.B.229.237; 13.B.229.238; 13.B.229.239;13.B.229.154; 13.B.229.157; 13.B.229.166; 13.B.229.169; 13.B.229.172;13.B.229.175; 13.B.229.240; 13.B.229.244; 13.B.230.228; 13.B.230.229;13.B.230.230; 13.B.230.231; 13.B.230.236; 13.B.230.237; 13.B.230.238;13.B.230.239; 13.B.230.154; 13.B.230.157; 13.B.230.166; 13.B.230.169;13.B.230.172; 13.B.230.175; 13.B.230.240; 13.B.230.244; 13.B.231.228;13.B.231.229; 13.B.231.230; 13.B.231.231; 13.B.231.236; 13.B.231.237;13.B.231.238; 13.B.231.239; 13.B.231.154; 13.B.231.157; 13.B.231.166;13.B.231.169; 13.B.231.172; 13.B.231.175; 13.B.231.240; 13.B.231.244;13.B.236.228; 13.B.236.229; 13.B.236.230; 13.B.236.231; 13.B.236.236;13.B.236.237; 13.B.236.238; 13.B.236.239; 13.B.236.154; 13.B.236.157;13.B.236.166; 13.B.236.169; 13.B.236.172; 13.B.236.175; 13.B.236.240;13.B.236.244; 13.B.237.228; 13.B.237.229; 13.B.237.230; 13.B.237.231;13.B.237.236; 13.B.237.237; 13.B.237.238; 13.B.237.239; 13.B.237.154;13.B.237.157; 13.B.237.166; 13.B.237.169; 13.B.237.172; 13.B.237.175;13.B.237.240; 13.B.237.244; 13.B.238.228; 13.B.238.229; 13.B.238.230;13.B.238.231; 13.B.238.236; 13.B.238.237; 13.B.238.238; 13.B.238.239;13.B.238.154; 13.B.238.157; 13.B.238.166; 13.B.238.169; 13.B.238.172;13.B.238.175; 13.B.238.240; 13.B.238.244; 13.B.239.228; 13.B.239.229;13.B.239.230; 13.B.239.231; 13.B.239.236; 13.B.239.237; 13.B.239.238;13.B.239.239; 13.B.239.154; 13.B.239.157; 13.B.239.166; 13.B.239.169;13.B.239.172; 13.B.239.175; 13.B.239.240; 13.B.239.244; 13.B.154.228;13.B.154.229; 13.B.154.230; 13.B.154.231; 13.B.154.236; 13.B.154.237;13.B.154.238; 13.B.154.239; 13.B.154.154; 13.B.154.157; 13.B.154.166;13.B.154.169; 13.B.154.172; 13.B.154.175; 13.B.154.240; 13.B.154.244;13.B.157.228; 13.B.157.229; 13.B.157.230; 13.B.157.231; 13.B.157.236;13.B.157.237; 13.B.157.238; 13.B.157.239; 13.B.157.154; 13.B.157.157;13.B.157.166; 13.B.157.169; 13.B.157.172; 13.B.157.175; 13.B.157.240;13.B.157.244; 13.B.166.228; 13.B.166.229; 13.B.166.230; 13.B.166.231;13.B.166.236; 13.B.166.237; 13.B.166.238; 13.B.166.239; 13.B.166.154;13.B.166.157; 13.B.166.166; 13.B.166.169; 13.B.166.172; 13.B.166.175;13.B.166.240; 13.B.166.244; 13.B.169.228; 13.B.169.229; 13.B.169.230;13.B.169.231; 13.B.169.236; 13.B.169.237; 13.B.169.238; 13.B.169.239;13.B.169.154; 13.B.169.157; 13.B.169.166; 13.B.169.169; 13.B.169.172;13.B.169.175; 13.B.169.240; 13.B.169.244; 13.B.172.228; 13.B.172.229;13.B.172.230; 13.B.172.231; 13.B.172.236; 13.B.172.237; 13.B.172.238;13.B.172.239; 13.B.172.154; 13.B.172.157; 13.B.172.166; 13.B.172.169;13.B.172.172; 13.B.172.175; 13.B.172.240; 13.B.172.244; 13.B.175.228;13.B.175.229; 13.B.175.230; 13.B.175.231; 13.B.175.236; 13.B.175.237;13.B.175.238; 13.B.175.239; 13.B.175.154; 13.B.175.157; 13.B.175.166;13.B.175.169; 13.B.175.172; 13.B.175.175; 13.B.175.240; 13.B.175.244;13.B.240.228; 13.B.240.229; 13.B.240.230; 13.B.240.231; 13.B.240.236;13.B.240.237; 13.B.240.238; 13.B.240.239; 13.B.240.154; 13.B.240.157;13.B.240.166; 13.B.240.169; 13.B.240.172; 13.B.240.175; 13.B.240.240;13.B.240.244; 13.B.244.228; 13.B.244.229; 13.B.244.230; 13.B.244.231;13.B.244.236; 13.B.244.237; 13.B.244.238; 13.B.244.239; 13.B.244.154;13.B.244.157; 13.B.244.166; 13.B.244.169; 13.B.244.172; 13.B.244.175;13.B.244.240; 13.B.244.244; Prodrugs of 13.D 13.D.228.228; 13.D.228.229;13.D.228.230; 13.D.228.231; 13.D.228.236; 13.D.228.237; 13.D.228.238;13.D.228.239; 13.D.228.154; 13.D.228.157; 13.D.228.166; 13.D.228.169;13.D.228.172; 13.D.228.175; 13.D.228.240; 13.D.228.244; 13.D.229.228;13.D.229.229; 13.D.229.230; 13.D.229.231; 13.D.229.236; 13.D.229.237;13.D.229.238; 13.D.229.239; 13.D.229.154; 13.D.229.157; 13.D.229.166;13.D.229.169; 13.D.229.172; 13.D.229.175; 13.D.229.240; 13.D.229.244;13.D.230.228; 13.D.230.229; 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13.D.169.237;13.D.169.238; 13.D.169.239; 13.D.169.154; 13.D.169.157; 13.D.169.166;13.D.169.169; 13.D.169.172; 13.D.169.175; 13.D.169.240; 13.D.169.244;13.D.172.228; 13.D.172.229; 13.D.172.230; 13.D.172.231; 13.D.172.236;13.D.172.237; 13.D.172.238; 13.D.172.239; 13.D.172.154; 13.D.172.157;13.D.172.166; 13.D.172.169; 13.D.172.172; 13.D.172.175; 13.D.172.240;13.D.172.244; 13.D.175.228; 13.D.175.229; 13.D.175.230; 13.D.175.231;13.D.175.236; 13.D.175.237; 13.D.175.238; 13.D.175.239; 13.D.175.154;13.D.175.157; 13.D.175.166; 13.D.175.169; 13.D.175.172; 13.D.175.175;13.D.175.240; 13.D.175.244; 13.D.240.228; 13.D.240.229; 13.D.240.230;13.D.240.231; 13.D.240.236; 13.D.240.237; 13.D.240.238; 13.D.240.239;13.D.240.154; 13.D.240.157; 13.D.240.166; 13.D.240.169; 13.D.240.172;13.D.240.175; 13.D.240.240; 13.D.240.244; 13.D.244.228; 13.D.244.229;13.D.244.230; 13.D.244.231; 13.D.244.236; 13.D.244.237; 13.D.244.238;13.D.244.239; 13.D.244.154; 13.D.244.157; 13.D.244.166; 13.D.244.169;13.D.244.172; 13.D.244.175; 13.D.244.240; 13.D.244.244; Prodrugs of 13.E13.E.228.228; 13.E.228.229; 13.E.228.230; 13.E.228.231; 13.E.228.236;13.E.228.237; 13.E.228.238; 13.E.228.239; 13.E.228.154; 13.E.228.157;13.E.228.166; 13.E.228.169; 13.E.228.172; 13.E.228.175; 13.E.228.240;13.E.228.244; 13.E.229.228; 13.E.229.229; 13.E.229.230; 13.E.229.231;13.E.229.236; 13.E.229.237; 13.E.229.238; 13.E.229.239; 13.E.229.154;13.E.229.157; 13.E.229.166; 13.E.229.169; 13.E.229.172; 13.E.229.175;13.E.229.240; 13.E.229.244; 13.E.230.228; 13.E.230.229; 13.E.230.230;13.E.230.231; 13.E.230.236; 13.E.230.237; 13.E.230.238; 13.E.230.239;13.E.230.154; 13.E.230.157; 13.E.230.166; 13.E.230.169; 13.E.230.172;13.E.230.175; 13.E.230.240; 13.E.230.244; 13.E.231.228; 13.E.231.229;13.E.231.230; 13.E.231.231; 13.E.231.236; 13.E.231.237; 13.E.231.238;13.E.231.239; 13.E.231.154; 13.E.231.157; 13.E.231.166; 13.E.231.169;13.E.231.172; 13.E.231.175; 13.E.231.240; 13.E.231.244; 13.E.236.228;13.E.236.229; 13.E.236.230; 13.E.236.231; 13.E.236.236; 13.E.236.237;13.E.236.238; 13.E.236.239; 13.E.236.154; 13.E.236.157; 13.E.236.166;13.E.236.169; 13.E.236.172; 13.E.236.175; 13.E.236.240; 13.E.236.244;13.E.237.228; 13.E.237.229; 13.E.237.230; 13.E.237.231; 13.E.237.236;13.E.237.237; 13.E.237.238; 13.E.237.239; 13.E.237.154; 13.E.237.157;13.E.237.166; 13.E.237.169; 13.E.237.172; 13.E.237.175; 13.E.237.240;13.E.237.244; 13.E.238.228; 13.E.238.229; 13.E.238.230; 13.E.238.231;13.E.238.236; 13.E.238.237; 13.E.238.238; 13.E.238.239; 13.E.238.154;13.E.238.157; 13.E.238.166; 13.E.238.169; 13.E.238.172; 13.E.238.175;13.E.238.240; 13.E.238.244; 13.E.239.228; 13.E.239.229; 13.E.239.230;13.E.239.231; 13.E.239.236; 13.E.239.237; 13.E.239.238; 13.E.239.239;13.E.239.154; 13.E.239.157; 13.E.239.166; 13.E.239.169; 13.E.239.172;13.E.239.175; 13.E.239.240; 13.E.239.244; 13.E.154.228; 13.E.154.229;13.E.154.230; 13.E.154.231; 13.E.154.236; 13.E.154.237; 13.E.154.238;13.E.154.239; 13.E.154.154; 13.E.154.157; 13.E.154.166; 13.E.154.169;13.E.154.172; 13.E.154.175; 13.E.154.240; 13.E.154.244; 13.E.157.228;13.E.157.229; 13.E.157.230; 13.E.157.231; 13.E.157.236; 13.E.157.237;13.E.157.238; 13.E.157.239; 13.E.157.154; 13.E.157.157; 13.E.157.166;13.E.157.169; 13.E.157.172; 13.E.157.175; 13.E.157.240; 13.E.157.244;13.E.166.228; 13.E.166.229; 13.E.166.230; 13.E.166.231; 13.E.166.236;13.E.166.237; 13.E.166.238; 13.E.166.239; 13.E.166.154; 13.E.166.157;13.E.166.166; 13.E.166.169; 13.E.166.172; 13.E.166.175; 13.E.166.240;13.E.166.244; 13.E.169.228; 13.E.169.229; 13.E.169.230; 13.E.169.231;13.E.169.236; 13.E.169.237; 13.E.169.238; 13.E.169.239; 13.E.169.154;13.E.169.157; 13.E.169.166; 13.E.169.169; 13.E.169.172; 13.E.169.175;13.E.169.240; 13.E.169.244; 13.E.172.228; 13.E.172.229; 13.E.172.230;13.E.172.231; 13.E.172.236; 13.E.172.237; 13.E.172.238; 13.E.172.239;13.E.172.154; 13.E.172.157; 13.E.172.166; 13.E.172.169; 13.E.172.172;13.E.172.175; 13.E.172.240; 13.E.172.244; 13.E.175.228; 13.E.175.229;13.E.175.230; 13.E.175.231; 13.E.175.236; 13.E.175.237; 13.E.175.238;13.E.175.239; 13.E.175.154; 13.E.175.157; 13.E.175.166; 13.E.175.169;13.E.175.172; 13.E.175.175; 13.E.175.240; 13.E.175.244; 13.E.240.228;13.E.240.229; 13.E.240.230; 13.E.240.231; 13.E.240.236; 13.E.240.237;13.E.240.238; 13.E.240.239; 13.E.240.154; 13.E.240.157; 13.E.240.166;13.E.240.169; 13.E.240.172; 13.E.240.175; 13.E.240.240; 13.E.240.244;13.E.244.228; 13.E.244.229; 13.E.244.230; 13.E.244.231; 13.E.244.236;13.E.244.237; 13.E.244.238; 13.E.244.239; 13.E.244.154; 13.E.244.157;13.E.244.166; 13.E.244.169; 13.E.244.172; 13.E.244.175; 13.E.244.240;13.E.244.244; Prodrugs of 13.G 13.G.228.228; 13.G.228.229; 13.G.228.230;13.G.228.231; 13.G.228.236; 13.G.228.237; 13.G.228.238; 13.G.228.239;13.G.228.154; 13.G.228.157; 13.G.228.166; 13.G.228.169; 13.G.228.172;13.G.228.175; 13.G.228.240; 13.G.228.244; 13.G.229.228; 13.G.229.229;13.G.229.230; 13.G.229.231; 13.G.229.236; 13.G.229.237; 13.G.229.238;13.G.229.239; 13.G.229.154; 13.G.229.157; 13.G.229.166; 13.G.229.169;13.G.229.172; 13.G.229.175; 13.G.229.240; 13.G.229.244; 13.G.230.228;13.G.230.229; 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13.U.244.172; 13.U.244.175; 13.U.244.240; 13.U.244.244;Prodrugs of 13.W 13.W.228.228; 13.W.228.229; 13.W.228.230; 13.W.228.231;13.W.228.236; 13.W.228.237; 13.W.228.238; 13.W.228.239; 13.W.228.154;13.W.228.157; 13.W.228.166; 13.W.228.169; 13.W.228.172; 13.W.228.175;13.W.228.240; 13.W.228.244; 13.W.229.228; 13.W.229.229; 13.W.229.230;13.W.229.231; 13.W.229.236; 13.W.229.237; 13.W.229.238; 13.W.229.239;13.W.229.154; 13.W.229.157; 13.W.229.166; 13.W.229.169; 13.W.229.172;13.W.229.175; 13.W.229.240; 13.W.229.244; 13.W.230.228; 13.W.230.229;13.W.230.230; 13.W.230.231; 13.W.230.236; 13.W.230.237; 13.W.230.238;13.W.230.239; 13.W.230.154; 13.W.230.157; 13.W.230.166; 13.W.230.169;13.W.230.172; 13.W.230.175; 13.W.230.240; 13.W.230.244; 13.W.231.228;13.W.231.229; 13.W.231.230; 13.W.231.231; 13.W.231.236; 13.W.231.237;13.W.231.238; 13.W.231.239; 13.W.231.154; 13.W.231.157; 13.W.231.166;13.W.231.169; 13.W.231.172; 13.W.231.175; 13.W.231.240; 13.W.231.244;13.W.236.228; 13.W.236.229; 13.W.236.230; 13.W.236.231; 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13.W.154.175; 13.W.154.240; 13.W.154.244;13.W.157.228; 13.W.157.229; 13.W.157.230; 13.W.157.231; 13.W.157.236;13.W.157.237; 13.W.157.238; 13.W.157.239; 13.W.157.154; 13.W.157.157;13.W.157.166; 13.W.157.169; 13.W.157.172; 13.W.157.175; 13.W.157.240;13.W.157.244; 13.W.166.228; 13.W.166.229; 13.W.166.230; 13.W.166.231;13.W.166.236; 13.W.166.237; 13.W.166.238; 13.W.166.239; 13.W.166.154;13.W.166.157; 13.W.166.166; 13.W.166.169; 13.W.166.172; 13.W.166.175;13.W.166.240; 13.W.166.244; 13.W.169.228; 13.W.169.229; 13.W.169.230;13.W.169.231; 13.W.169.236; 13.W.169.237; 13.W.169.238; 13.W.169.239;13.W.169.154; 13.W.169.157; 13.W.169.166; 13.W.169.169; 13.W.169.172;13.W.169.175; 13.W.169.240; 13.W.169.244; 13.W.172.228; 13.W.172.229;13.W.172.230; 13.W.172.231; 13.W.172.236; 13.W.172.237; 13.W.172.238;13.W.172.239; 13.W.172.154; 13.W.172.157; 13.W.172.166; 13.W.172.169;13.W.172.172; 13.W.172.175; 13.W.172.240; 13.W.172.244; 13.W.175.228;13.W.175.229; 13.W.175.230; 13.W.175.231; 13.W.175.236; 13.W.175.237;13.W.175.238; 13.W.175.239; 13.W.175.154; 13.W.175.157; 13.W.175.166;13.W.175.169; 13.W.175.172; 13.W.175.175; 13.W.175.240; 13.W.175.244;13.W.240.228; 13.W.240.229; 13.W.240.230; 13.W.240.231; 13.W.240.236;13.W.240.237; 13.W.240.238; 13.W.240.239; 13.W.240.154; 13.W.240.157;13.W.240.166; 13.W.240.169; 13.W.240.172; 13.W.240.175; 13.W.240.240;13.W.240.244; 13.W.244.228; 13.W.244.229; 13.W.244.230; 13.W.244.231;13.W.244.236; 13.W.244.237; 13.W.244.238; 13.W.244.239; 13.W.244.154;13.W.244.157; 13.W.244.166; 13.W.244.169; 13.W.244.172; 13.W.244.175;13.W.244.240; 13.W.244.244; Prodrugs of 13.Y 13.Y.228.228; 13.Y.228.229;13.Y.228.230; 13.Y.228.231; 13.Y.228.236; 13.Y.228.237; 13.Y.228.238;13.Y.228.239; 13.Y.228.154; 13.Y.228.157; 13.Y.228.166; 13.Y.228.169;13.Y.228.172; 13.Y.228.175; 13.Y.228.240; 13.Y.228.244; 13.Y.229.228;13.Y.229.229; 13.Y.229.230; 13.Y.229.231; 13.Y.229.236; 13.Y.229.237;13.Y.229.238; 13.Y.229.239; 13.Y.229.154; 13.Y.229.157; 13.Y.229.166;13.Y.229.169; 13.Y.229.172; 13.Y.229.175; 13.Y.229.240; 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13.Y.169.230; 13.Y.169.231; 13.Y.169.236; 13.Y.169.237;13.Y.169.238; 13.Y.169.239; 13.Y.169.154; 13.Y.169.157; 13.Y.169.166;13.Y.169.169; 13.Y.169.172; 13.Y.169.175; 13.Y.169.240; 13.Y.169.244;13.Y.172.228; 13.Y.172.229; 13.Y.172.230; 13.Y.172.231; 13.Y.172.236;13.Y.172.237; 13.Y.172.238; 13.Y.172.239; 13.Y.172.154; 13.Y.172.157;13.Y.172.166; 13.Y.172.169; 13.Y.172.172; 13.Y.172.175; 13.Y.172.240;13.Y.172.244; 13.Y.175.228; 13.Y.175.229; 13.Y.175.230; 13.Y.175.231;13.Y.175.236; 13.Y.175.237; 13.Y.175.238; 13.Y.175.239; 13.Y.175.154;13.Y.175.157; 13.Y.175.166; 13.Y.175.169; 13.Y.175.172; 13.Y.175.175;13.Y.175.240; 13.Y.175.244; 13.Y.240.228; 13.Y.240.229; 13.Y.240.230;13.Y.240.231; 13.Y.240.236; 13.Y.240.237; 13.Y.240.238; 13.Y.240.239;13.Y.240.154; 13.Y.240.157; 13.Y.240.166; 13.Y.240.169; 13.Y.240.172;13.Y.240.175; 13.Y.240.240; 13.Y.240.244; 13.Y.244.228; 13.Y.244.229;13.Y.244.230; 13.Y.244.231; 13.Y.244.236; 13.Y.244.237; 13.Y.244.238;13.Y.244.239; 13.Y.244.154; 13.Y.244.157; 13.Y.244.166; 13.Y.244.169;13.Y.244.172; 13.Y.244.175; 13.Y.244.240; 13.Y.244.244; Prodrugs of14.AH 14.AH.4.157; 14.AH.4.158; 14.AH.4.196; 14.AH.4.223; 14.AH.4.240;14.AH.4.244; 14.AH.4.243; 14.AH.4.247; 14.AH.5.157; 14.AH.5.158;14.AH.5.196; 14.AH.5.223; 14.AH.5.240; 14.AH.5.244; 14.AH.5.243;14.AH.5.247; 14.AH.7.157; 14.AH.7.158; 14.AH.7.196; 14.AH.7.223;14.AH.7.240; 14.AH.7.244; 14.AH.7.243; 14.AH.7.247; 14.AH.15.157;14.AH.15.158; 14.AH.15.196; 14.AH.15.223; 14.AH.15.240; 14.AH.15.244;14.AH.15.243; 14.AH.15.247; 14.AH.16.157; 14.AH.16.158; 14.AH.16.196;14.AH.16.223; 14.AH.16.240; 14.AH.16.244; 14.AH.16.243; 14.AH.16.247;14.AH.18.157; 14.AH.18.158; 14.AH.18.196; 14.AH.18.223; 14.AH.18.240;14.AH.18.244; 14.AH.18.243; 14.AH.18.247; 14.AH.26.157; 14.AH.26.158;14.AH.26.196; 14.AH.26.223; 14.AH.26.240; 14.AH.26.244; 14.AH.26.243;14.AH.26.247; 14.AH.27.157; 14.AH.27.158; 14.AH.27.196; 14.AH.27.223;14.AH.27.240; 14.AH.27.244; 14.AH.27.243; 14.AH.27.247; 14.AH.29.157;14.AH.29.158; 14.AH.29.196; 14.AH.29.223; 14.AH.29.240; 14.AH.29.244;14.AH.29.243; 14.AH.29.247; 14.AH.54.157; 14.AH.54.158; 14.AH.54.196;14.AH.54.223; 14.AH.54.240; 14.AH.54.244; 14.AH.54.243; 14.AH.54.247;14.AH.55.157; 14.AH.55.158; 14.AH.55.196; 14.AH.55.223; 14.AH.55.240;14.AH.55.244; 14.AH.55.243; 14.AH.55.247; 14.AH.56.157; 14.AH.56.158;14.AH.56.196; 14.AH.56.223; 14.AH.56.240; 14.AH.56.244; 14.AH.56.243;14.AH.56.247; 14.AH.157.157; 14.AH.157.158; 14.AH.157.196;14.AH.157.223; 14.AH.157.240; 14.AH.157.244; 14.AH.157.243;14.AH.157.247; 14.AH.196.157; 14.AH.196.158; 14.AH.196.196;14.AH.196.223; 14.AH.196.240; 14.AH.196.244; 14.AH.196.243;14.AH.196.247; 14.AH.223.157; 14.AH.223.158; 14.AH.223.196;14.AH.223.223; 14.AH.223.240; 14.AH.223.244; 14.AH.223.243;14.AH.223.247; 14.AH.240.157; 14.AH.240.158; 14.AH.240.196;14.AH.240.223; 14.AH.240.240; 14.AH.240.244; 14.AH.240.243;14.AH.240.247; 14.AH.244.157; 14.AH.244.158; 14.AH.244.196;14.AH.244.223; 14.AH.244.240; 14.AH.244.244; 14.AH.244.243;14.AH.244.247; 14.AH.247.157; 14.AH.247.158; 14.AH.247.196;14.AH.247.223; 14.AH.247.240; 14.AH.247.244; 14.AH.247.243;14.AH.247.247; Prodrugs of 14.AJ 14.AJ.4.157; 14.AJ.4.158; 14.AJ.4.196;14.AJ.4.223; 14.AJ.4.240; 14.AJ.4.244; 14.AJ.4.243; 14.AJ.4.247;14.AJ.5.157; 14.AJ.5.158; 14.AJ.5.196; 14.AJ.5.223; 14.AJ.5.240;14.AJ.5.244; 14.AJ.5.243; 14.AJ.5.247; 14.AJ.7.157; 14.AJ.7.158;14.AJ.7.196; 14.AJ.7.223; 14.AJ.7.240; 14.AJ.7.244; 14.AJ.7.243;14.AJ.7.247; 14.AJ.15.157; 14.AJ.15.158; 14.AJ.15.196; 14.AJ.15.223;14.AJ.15.240; 14.AJ.15.244; 14.AJ.15.243; 14.AJ.15.247; 14.AJ.16.157;14.AJ.16.158; 14.AJ.16.196; 14.AJ.16.223; 14.AJ.16.240; 14.AJ.16.244;14.AJ.16.243; 14.AJ.16.247; 14.AJ.18.157; 14.AJ.18.158; 14.AJ.18.196;14.AJ.18.223; 14.AJ.18.240; 14.AJ.18.244; 14.AJ.18.243; 14.AJ.18.247;14.AJ.26.157; 14.AJ.26.158; 14.AJ.26.196; 14.AJ.26.223; 14.AJ.26.240;14.AJ.26.244; 14.AJ.26.243; 14.AJ.26.247; 14.AJ.27.157; 14.AJ.27.158;14.AJ.27.196; 14.AJ.27.223; 14.AJ.27.240; 14.AJ.27.244; 14.AJ.27.243;14.AJ.27.247; 14.AJ.29.157; 14.AJ.29.158; 14.AJ.29.196; 14.AJ.29.223;14.AJ.29.240; 14.AJ.29.244; 14.AJ.29.243; 14.AJ.29.247; 14.AJ.54.157;14.AJ.54.158; 14.AJ.54.196; 14.AJ.54.223; 14.AJ.54.240; 14.AJ.54.244;14.AJ.54.243; 14.AJ.54.247; 14.AJ.55.157; 14.AJ.55.158; 14.AJ.55.196;14.AJ.55.223; 14.AJ.55.240; 14.AJ.55.244; 14.AJ.55.243; 14.AJ.55.247;14.AJ.56.157; 14.AJ.56.158; 14.AJ.56.196; 14.AJ.56.223; 14.AJ.56.240;14.AJ.56.244; 14.AJ.56.243; 14.AJ.56.247; 14.AJ.157.157; 14.AJ.157.158;14.AJ.157.196; 14.AJ.157.223; 14.AJ.157.240; 14.AJ.157.244;14.AJ.157.243; 14.AJ.157.247; 14.AJ.196.157; 14.AJ.196.158;14.AJ.196.196; 14.AJ.196.223; 14.AJ.196.240; 14.AJ.196.244;14.AJ.196.243; 14.AJ.196.247; 14.AJ.223.157; 14.AJ.223.158;14.AJ.223.196; 14.AJ.223.223; 14.AJ.223.240; 14.AJ.223.244;14.AJ.223.243; 14.AJ.223.247; 14.AJ.240.157; 14.AJ.240.158;14.AJ.240.196; 14.AJ.240.223; 14.AJ.240.240; 14.AJ.240.244;14.AJ.240.243; 14.AJ.240.247; 14.AJ.244.157; 14.AJ.244.158;14.AJ.244.196; 14.AJ.244.223; 14.AJ.244.240; 14.AJ.244.244;14.AJ.244.243; 14.AJ.244.247; 14.AJ.247.157; 14.AJ.247.158;14.AJ.247.196; 14.AJ.247.223; 14.AJ.247.240; 14.AJ.247.244;14.AJ.247.243; 14.AJ.247.247; Prodrugs of 14.AN 14.AN.4.157;14.AN.4.158; 14.AN.4.196; 14.AN.4.223; 14.AN.4.240; 14.AN.4.244;14.AN.4.243; 14.AN.4.247; 14.AN.5.157; 14.AN.5.158; 14.AN.5.196;14.AN.5.223; 14.AN.5.240; 14.AN.5.244; 14.AN.5.243; 14.AN.5.247;14.AN.7.157; 14.AN.7.158; 14.AN.7.196; 14.AN.7.223; 14.AN.7.240;14.AN.7.244; 14.AN.7.243; 14.AN.7.247; 14.AN.15.157; 14.AN.15.158;14.AN.15.196; 14.AN.15.223; 14.AN.15.240; 14.AN.15.244; 14.AN.15.243;14.AN.15.247; 14.AN.16.157; 14.AN.16.158; 14.AN.16.196; 14.AN.16.223;14.AN.16.240; 14.AN.16.244; 14.AN.16.243; 14.AN.16.247; 14.AN.18.157;14.AN.18.158; 14.AN.18.196; 14.AN.18.223; 14.AN.18.240; 14.AN.18.244;14.AN.18.243; 14.AN.18.247; 14.AN.26.157; 14.AN.26.158; 14.AN.26.196;14.AN.26.223; 14.AN.26.240; 14.AN.26.244; 14.AN.26.243; 14.AN.26.247;14.AN.27.157; 14.AN.27.158; 14.AN.27.196; 14.AN.27.223; 14.AN.27.240;14.AN.27.244; 14.AN.27.243; 14.AN.27.247; 14.AN.29.157; 14.AN.29.158;14.AN.29.196; 14.AN.29.223; 14.AN.29.240; 14.AN.29.244; 14.AN.29.243;14.AN.29.247; 14.AN.54.157; 14.AN.54.158; 14.AN.54.196; 14.AN.54.223;14.AN.54.240; 14.AN.54.244; 14.AN.54.243; 14.AN.54.247; 14.AN.55.157;14.AN.55.158; 14.AN.55.196; 14.AN.55.223; 14.AN.55.240; 14.AN.55.244;14.AN.55.243; 14.AN.55.247; 14.AN.56.157; 14.AN.56.158; 14.AN.56.196;14.AN.56.223; 14.AN.56.240; 14.AN.56.244; 14.AN.56.243; 14.AN.56.247;14.AN.157.157; 14.AN.157.158; 14.AN.157.196; 14.AN.157.223;14.AN.157.240; 14.AN.157.244; 14.AN.157.243; 14.AN.157.247;14.AN.196.157; 14.AN.196.158; 14.AN.196.196; 14.AN.196.223;14.AN.196.240; 14.AN.196.244; 14.AN.196.243; 14.AN.196.247;14.AN.223.157; 14.AN.223.158; 14.AN.223.196; 14.AN.223.223;14.AN.223.240; 14.AN.223.244; 14.AN.223.243; 14.AN.223.247;14.AN.240.157; 14.AN.240.158; 14.AN.240.196; 14.AN.240.223;14.AN.240.240; 14.AN.240.244; 14.AN.240.243; 14.AN.240.247;14.AN.244.157; 14.AN.244.158; 14.AN.244.196; 14.AN.244.223;14.AN.244.240; 14.AN.244.244; 14.AN.244.243; 14.AN.244.247;14.AN.247.157; 14.AN.247.158; 14.AN.247.196; 14.AN.247.223;14.AN.247.240; 14.AN.247.244; 14.AN.247.243; 14.AN.247.247; Prodrugs of14.AP 14.AP.4.157; 14.AP.4.158; 14.AP.4.196; 14.AP.4.223; 14.AP.4.240;14.AP.4.244; 14.AP.4.243; 14.AP.4.247; 14.AP.5.157; 14.AP.5.158;14.AP.5.196; 14.AP.5.223; 14.AP.5.240; 14.AP.5.244; 14.AP.5.243;14.AP.5.247; 14.AP.7.157; 14.AP.7.158; 14.AP.7.196; 14.AP.7.223;14.AP.7.240; 14.AP.7.244; 14.AP.7.243; 14.AP.7.247; 14.AP.15.157;14.AP.15.158; 14.AP.15.196; 14.AP.15.223; 14.AP.15.240; 14.AP.15.244;14.AP.15.243; 14.AP.15.247; 14.AP.16.157; 14.AP.16.158; 14.AP.16.196;14.AP.16.223; 14.AP.16.240; 14.AP.16.244; 14.AP.16.243; 14.AP.16.247;14.AP.18.157; 14.AP.18.158; 14.AP.18.196; 14.AP.18.223; 14.AP.18.240;14.AP.18.244; 14.AP.18.243; 14.AP.18.247; 14.AP.26.157; 14.AP.26.158;14.AP.26.196; 14.AP.26.223; 14.AP.26.240; 14.AP.26.244; 14.AP.26.243;14.AP.26.247; 14.AP.27.157; 14.AP.27.158; 14.AP.27.196; 14.AP.27.223;14.AP.27.240; 14.AP.27.244; 14.AP.27.243; 14.AP.27.247; 14.AP.29.157;14.AP.29.158; 14.AP.29.196; 14.AP.29.223; 14.AP.29.240; 14.AP.29.244;14.AP.29.243; 14.AP.29.247; 14.AP.54.157; 14.AP.54.158; 14.AP.54.196;14.AP.54.223; 14.AP.54.240; 14.AP.54.244; 14.AP.54.243; 14.AP.54.247;14.AP.55.157; 14.AP.55.158; 14.AP.55.196; 14.AP.55.223; 14.AP.55.240;14.AP.55.244; 14.AP.55.243; 14.AP.55.247; 14.AP.56.157; 14.AP.56.158;14.AP.56.196; 14.AP.56.223; 14.AP.56.240; 14.AP.56.244; 14.AP.56.243;14.AP.56.247; 14.AP.157.157; 14.AP.157.158; 14.AP.157.196;14.AP.157.223; 14.AP.157.240; 14.AP.157.244; 14.AP.157.243;14.AP.157.247; 14.AP.196.157; 14.AP.196.158; 14.AP.196.196;14.AP.196.223; 14.AP.196.240; 14.AP.196.244; 14.AP.196.243;14.AP.196.247; 14.AP.223.157; 14.AP.223.158; 14.AP.223.196;14.AP.223.223; 14.AP.223.240; 14.AP.223.244; 14.AP.223.243;14.AP.223.247; 14.AP.240.157; 14.AP.240.158; 14.AP.240.196;14.AP.240.223; 14.AP.240.240; 14.AP.240.244; 14.AP.240.243;14.AP.240.247; 14.AP.244.157; 14.AP.244.158; 14.AP.244.196;14.AP.244.223; 14.AP.244.240; 14.AP.244.244; 14.AP.244.243;14.AP.244.247; 14.AP.247.157; 14.AP.247.158; 14.AP.247.196;14.AP.247.223; 14.AP.247.240; 14.AP.247.244; 14.AP.247.243;14.AP.247.247; Prodrugs of 14.AZ 14.AZ.4.157; 14.AZ.4.158; 14.AZ.4.196;14.AZ.4.223; 14.AZ.4.240; 14.AZ.4.244; 14.AZ.4.243; 14.AZ.4.247;14.AZ.5.157; 14.AZ.5.158; 14.AZ.5.196; 14.AZ.5.223; 14.AZ.5.240;14.AZ.5.244; 14.AZ.5.243; 14.AZ.5.247; 14.AZ.7.157; 14.AZ.7.158;14.AZ.7.196; 14.AZ.7.223; 14.AZ.7.240; 14.AZ.7.244; 14.AZ.7.243;14.AZ.7.247; 14.AZ.15.157; 14.AZ.15.158; 14.AZ.15.196; 14.AZ.15.223;14.AZ.15.240; 14.AZ.15.244; 14.AZ.15.243; 14.AZ.15.247; 14.AZ.16.157;14.AZ.16.158; 14.AZ.16.196; 14.AZ.16.223; 14.AZ.16.240; 14.AZ.16.244;14.AZ.16.243; 14.AZ.16.247; 14.AZ.18.157; 14.AZ.18.158; 14.AZ.18.196;14.AZ.18.223; 14.AZ.18.240; 14.AZ.18.244; 14.AZ.18.243; 14.AZ.18.247;14.AZ.26.157; 14.AZ.26.158; 14.AZ.26.196; 14.AZ.26.223; 14.AZ.26.240;14.AZ.26.244; 14.AZ.26.243; 14.AZ.26.247; 14.AZ.27.157; 14.AZ.27.158;14.AZ.27.196; 14.AZ.27.223; 14.AZ.27.240; 14.AZ.27.244; 14.AZ.27.243;14.AZ.27.247; 14.AZ.29.157; 14.AZ.29.158; 14.AZ.29.196; 14.AZ.29.223;14.AZ.29.240; 14.AZ.29.244; 14.AZ.29.243; 14.AZ.29.247; 14.AZ.54.157;14.AZ.54.158; 14.AZ.54.196; 14.AZ.54.223; 14.AZ.54.240; 14.AZ.54.244;14.AZ.54.243; 14.AZ.54.247; 14.AZ.55.157; 14.AZ.55.158; 14.AZ.55.196;14.AZ.55.223; 14.AZ.55.240; 14.AZ.55.244; 14.AZ.55.243; 14.AZ.55.247;14.AZ.56.157; 14.AZ.56.158; 14.AZ.56.196; 14.AZ.56.223; 14.AZ.56.240;14.AZ.56.244; 14.AZ.56.243; 14.AZ.56.247; 14.AZ.157.157; 14.AZ.157.158;14.AZ.157.196; 14.AZ.157.223; 14.AZ.157.240; 14.AZ.157.244;14.AZ.157.243; 14.AZ.157.247; 14.AZ.196.157; 14.AZ.196.158;14.AZ.196.196; 14.AZ.196.223; 14.AZ.196.240; 14.AZ.196.244;14.AZ.196.243; 14.AZ.196.247; 14.AZ.223.157; 14.AZ.223.158;14.AZ.223.196; 14.AZ.223.223; 14.AZ.223.240; 14.AZ.223.244;14.AZ.223.243; 14.AZ.223.247; 14.AZ.240.157; 14.AZ.240.158;14.AZ.240.196; 14.AZ.240.223; 14.AZ.240.240; 14.AZ.240.244;14.AZ.240.243; 14.AZ.240.247; 14.AZ.244.157; 14.AZ.244.158;14.AZ.244.196; 14.AZ.244.223; 14.AZ.244.240; 14.AZ.244.244;14.AZ.244.243; 14.AZ.244.247; 14.AZ.247.157; 14.AZ.247.158;14.AZ.247.196; 14.AZ.247.223; 14.AZ.247.240; 14.AZ.247.244;14.AZ.247.243; 14.AZ.247.247; Prodrugs of 14.BF 14.BF.4.157;14.BF.4.158; 14.BF.4.196; 14.BF.4.223; 14.BF.4.240; 14.BF.4.244;14.BF.4.243; 14.BF.4.247; 14.BF.5.157; 14.BF.5.158; 14.BF.5.196;14.BF.5.223; 14.BF.5.240; 14.BF.5.244; 14.BF.5.243; 14.BF.5.247;14.BF.7.157; 14.BF.7.158; 14.BF.7.196; 14.BF.7.223; 14.BF.7.240;14.BF.7.244; 14.BF.7.243; 14.BF.7.247; 14.BF.15.157; 14.BF.15.158;14.BF.15.196; 14.BF.15.223; 14.BF.15.240; 14.BF.15.244; 14.BF.15.243;14.BF.15.247; 14.BF.16.157; 14.BF.16.158; 14.BF.16.196; 14.BF.16.223;14.BF.16.240; 14.BF.16.244; 14.BF.16.243; 14.BF.16.247; 14.BF.18.157;14.BF.18.158; 14.BF.18.196; 14.BF.18.223; 14.BF.18.240; 14.BF.18.244;14.BF.18.243; 14.BF.18.247; 14.BF.26.157; 14.BF.26.158; 14.BF.26.196;14.BF.26.223; 14.BF.26.240; 14.BF.26.244; 14.BF.26.243; 14.BF.26.247;14.BF.27.157; 14.BF.27.158; 14.BF.27.196; 14.BF.27.223; 14.BF.27.240;14.BF.27.244; 14.BF.27.243; 14.BF.27.247; 14.BF.29.157; 14.BF.29.158;14.BF.29.196; 14.BF.29.223; 14.BF.29.240; 14.BF.29.244; 14.BF.29.243;14.BF.29.247; 14.BF.54.157; 14.BF.54.158; 14.BF.54.196; 14.BF.54.223;14.BF.54.240; 14.BF.54.244; 14.BF.54.243; 14.BF.54.247; 14.BF.55.157;14.BF.55.158; 14.BF.55.196; 14.BF.55.223; 14.BF.55.240; 14.BF.55.244;14.BF.55.243; 14.BF.55.247; 14.BF.56.157; 14.BF.56.158; 14.BF.56.196;14.BF.56.223; 14.BF.56.240; 14.BF.56.244; 14.BF.56.243; 14.BF.56.247;14.BF.157.157; 14.BF.157.158; 14.BF.157.196; 14.BF.157.223;14.BF.157.240; 14.BF.157.244; 14.BF.157.243; 14.BF.157.247;14.BF.196.157; 14.BF.196.158; 14.BF.196.196; 14.BF.196.223;14.BF.196.240; 14.BF.196.244; 14.BF.196.243; 14.BF.196.247;14.BF.223.157; 14.BF.223.158; 14.BF.223.196; 14.BF.223.223;14.BF.223.240; 14.BF.223.244; 14.BF.223.243; 14.BF.223.247;14.BF.240.157; 14.BF.240.158; 14.BF.240.196; 14.BF.240.223;14.BF.240.240; 14.BF.240.244; 14.BF.240.243; 14.BF.240.247;14.BF.244.157; 14.BF.244.158; 14.BF.244.196; 14.BF.244.223;14.BF.244.240; 14.BF.244.244; 14.BF.244.243; 14.BF.244.247;14.BF.247.157; 14.BF.247.158; 14.BF.247.196; 14.BF.247.223;14.BF.247.240; 14.BF.247.244; 14.BF.247.243; 14.BF.247.247; Prodrugs of14.CI 14.CI.4.157; 14.CI.4.158; 14.CI.4.196; 14.CI.4.223; 14.CI.4.240;14.CI.4.244; 14.CI.4.243; 14.CI.4.247; 14.CI.5.157; 14.CI.5.158;14.CI.5.196; 14.CI.5.223; 14.CI.5.240; 14.CI.5.244; 14.CI.5.243;14.CI.5.247; 14.CI.7.157; 14.CI.7.158; 14.CI.7.196; 14.CI.7.223;14.CI.7.240; 14.CI.7.244; 14.CI.7.243; 14.CI.7.247; 14.CI.15.157;14.CI.15.158; 14.CI.15.196; 14.CI.15.223; 14.CI.15.240; 14.CI.15.244;14.CI.15.243; 14.CI.15.247; 14.CI.16.157; 14.CI.16.158; 14.CI.16.196;14.CI.16.223; 14.CI.16.240; 14.CI.16.244; 14.CI.16.243; 14.CI.16.247;14.CI.18.157; 14.CI.18.158; 14.CI.18.196; 14.CI.18.223; 14.CI.18.240;14.CI.18.244; 14.CI.18.243; 14.CI.18.247; 14.CI.26.157; 14.CI.26.158;14.CI.26.196; 14.CI.26.223; 14.CI.26.240; 14.CI.26.244; 14.CI.26.243;14.CI.26.247; 14.CI.27.157; 14.CI.27.158; 14.CI.27.196; 14.CI.27.223;14.CI.27.240; 14.CI.27.244; 14.CI.27.243; 14.CI.27.247; 14.CI.29.157;14.CI.29.158; 14.CI.29.196; 14.CI.29.223; 14.CI.29.240; 14.CI.29.244;14.CI.29.243; 14.CI.29.247; 14.CI.54.157; 14.CI.54.158; 14.CI.54.196;14.CI.54.223; 14.CI.54.240; 14.CI.54.244; 14.CI.54.243; 14.CI.54.247;14.CI.55.157; 14.CI.55.158; 14.CI.55.196; 14.CI.55.223; 14.CI.55.240;14.CI.55.244; 14.CI.55.243; 14.CI.55.247; 14.CI.56.157; 14.CI.56.158;14.CI.56.196; 14.CI.56.223; 14.CI.56.240; 14.CI.56.244; 14.CI.56.243;14.CI.56.247; 14.CI.157.157; 14.CI.157.158; 14.CI.157.196;14.CI.157.223; 14.CI.157.240; 14.CI.157.244; 14.CI.157.243;14.CI.157.247; 14.CI.196.157; 14.CI.196.158; 14.CI.196.196;14.CI.196.223; 14.CI.196.240; 14.CI.196.244; 14.CI.196.243;14.CI.196.247; 14.CI.223.157; 14.CI.223.158; 14.CI.223.196;14.CI.223.223; 14.CI.223.240; 14.CI.223.244; 14.CI.223.243;14.CI.223.247; 14.CI.240.157; 14.CI.240.158; 14.CI.240.196;14.CI.240.223; 14.CI.240.240; 14.CI.240.244; 14.CI.240.243;14.CI.240.247; 14.CI.244.157; 14.CI.244.158; 14.CI.244.196;14.CI.244.223; 14.CI.244.240; 14.CI.244.244; 14.CI.244.243;14.CI.244.247; 14.CI.247.157; 14.CI.247.158; 14.CI.247.196;14.CI.247.223; 14.CI.247.240; 14.CI.247.244; 14.CI.247.243;14.CI.247.247; Prodrugs of 14.CO 14.CO.4.157; 14.CO.4.158; 14.CO.4.196;14.CO.4.223; 14.CO.4.240; 14.CO.4.244; 14.CO.4.243; 14.CO.4.247;14.CO.5.157; 14.CO.5.158; 14.CO.5.196; 14.CO.5.223; 14.CO.5.240;14.CO.5.244; 14.CO.5.243; 14.CO.5.247; 14.CO.7.157; 14.CO.7.158;14.CO.7.196; 14.CO.7.223; 14.CO.7.240; 14.CO.7.244; 14.CO.7.243;14.CO.7.247; 14.CO.15.157; 14.CO.15.158; 14.CO.15.196; 14.CO.15.223;14.CO.15.240; 14.CO.15.244; 14.CO.15.243; 14.CO.15.247; 14.CO.16.157;14.CO.16.158; 14.CO.16.196; 14.CO.16.223; 14.CO.16.240; 14.CO.16.244;14.CO.16.243; 14.CO.16.247; 14.CO.18.157; 14.CO.18.158; 14.CO.18.196;14.CO.18.223; 14.CO.18.240; 14.CO.18.244; 14.CO.18.243; 14.CO.18.247;14.CO.26.157; 14.CO.26.158; 14.CO.26.196; 14.CO.26.223; 14.CO.26.240;14.CO.26.244; 14.CO.26.243; 14.CO.26.247; 14.CO.27.157; 14.CO.27.158;14.CO.27.196; 14.CO.27.223; 14.CO.27.240; 14.CO.27.244; 14.CO.27.243;14.CO.27.247; 14.CO.29.157; 14.CO.29.158; 14.CO.29.196; 14.CO.29.223;14.CO.29.240; 14.CO.29.244; 14.CO.29.243; 14.CO.29.247; 14.CO.54.157;14.CO.54.158; 14.CO.54.196; 14.CO.54.223; 14.CO.54.240; 14.CO.54.244;14.CO.54.243; 14.CO.54.247; 14.CO.55.157; 14.CO.55.158; 14.CO.55.196;14.CO.55.223; 14.CO.55.240; 14.CO.55.244; 14.CO.55.243; 14.CO.55.247;14.CO.56.157; 14.CO.56.158; 14.CO.56.196; 14.CO.56.223; 14.CO.56.240;14.CO.56.244; 14.CO.56.243; 14.CO.56.247; 14.CO.157.157; 14.CO.157.158;14.CO.157.196; 14.CO.157.223; 14.CO.157.240; 14.CO.157.244;14.CO.157.243; 14.CO.157.247; 14.CO.196.157; 14.CO.196.158;14.CO.196.196; 14.CO.196.223; 14.CO.196.240; 14.CO.196.244;14.CO.196.243; 14.CO.196.247; 14.CO.223.157; 14.CO.223.158;14.CO.223.196; 14.CO.223.223; 14.CO.223.240; 14.CO.223.244;14.CO.223.243; 14.CO.223.247; 14.CO.240.157; 14.CO.240.158;14.CO.240.196; 14.CO.240.223; 14.CO.240.240; 14.CO.240.244;14.CO.240.243; 14.CO.240.247; 14.CO.244.157; 14.CO.244.158;14.CO.244.196; 14.CO.244.223; 14.CO.244.240; 14.CO.244.244;14.CO.244.243; 14.CO.244.247; 14.CO.4.157; 14.CO.4.158; 14.CO.4.196;14.CO.4.223; 14.CO.4.240; 14.CO.4.244; 14.CO.4.243; 14.CO.4.247;

Prodrugs of 8.BF

All literature and patent citations above are hereby expresslyincorporated by reference at the locations of their citation.Specifically cited sections or pages of the above cited works areincorporated by reference with specificity. The invention has beendescribed in detail sufficient to allow one of ordinary skill in the artto make and use the subject matter of the following Claims. It isapparent that certain modifications of the methods and compositions ofthe following Claims can be made within the scope and spirit of theinvention.

In the claims hereinbelow, the subscript and superscripts of a givenvariable are distinct. For example, R₁ is distinct from R¹.

1. A conjugate of formula:[DRUG]-(A⁰)_(nn); wherein: DRUG is a compound of formula 546:

nn is 1, 2 or 3; A⁰ is A¹; A¹ is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x))); Y² is independently a bond, O,N(R^(x)), N(O)(R^(x)), N(OR^(x)), N(O)(OR^(x)), N(N(R^(x))(R^(x))),—S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—; and when Y² joins two phosphorousatoms Y² can also be C(R²)(R²); R^(x) is H; R¹ is independently H oralkyl of 1 to 18 carbon atoms; R² is independently H, R¹, R³ or R⁴wherein each R⁴ is independently substituted with 0 to 3 R³ groups ortaken together at a carbon atom, two R² groups form a ring of 3 to 8carbons and the ring may be substituted with 0 to 3 R³ groups; R³ isR^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is bound to aheteroatom, then R³ is R^(3c) or R^(3d); R^(3a) is F, Cl, Br, I, —CN, N₃or —NO₂; R^(3b) is Y¹; R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x),—S(O)R^(x), —S(O)₂R^(x), —S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x),—OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x))); R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or—C(Y¹)(N(R^(x))(R^(x))); R⁴ is an alkyl of 1 to 18 carbon atoms, alkenylof 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R⁵ is R⁴wherein each R⁴ is substituted with 0 to 3 R³ groups; W³ is W⁴ or W¹; W⁴is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO_(M2)R⁵, or —SO_(M2)W⁵; W⁵ is carbocyclewherein W⁵ is independently substituted with 0 to 3 R² groups; W⁶ is W³independently substituted with 1, 2, or 3 A3 groups; M2 is 0, 1 or 2;M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and M12b is 0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11 or 12; or a pharmaceutically acceptable salt orsolvate thereof.
 2. The conjugate of claim 1 wherein Y² is O.
 3. Theconjugate of claim 1 wherein each A³ is of the formula:


4. The conjugate of claim 1 wherein each A³ is of the formula:


5. The conjugate of claim 1 wherein each A³ is of the formula:

wherein: Y^(1a) is O or S; and Y^(2a) is O, N(R^(x)) or S.
 6. Theconjugate of claim 1 wherein each A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)).
 7. The conjugate of claim 1 whereineach A³ is of the formula:

wherein: Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.8. The conjugate of claim 1 wherein each A³ is of the formula:

wherein: Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.9. The conjugate of claim 1, wherein each A³ is of the formula:


10. The conjugate of claim 1 wherein A⁰ is of the formula:

wherein each R is independently alkyl.
 11. A pharmaceutical compositioncomprising a pharmaceutical excipient and a conjugate as described inclaim 1, or a pharmaceutically acceptable salt or solvate thereof.